166 results on '"Victor X. Jin"'
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2. Data from Interferon-Stimulated Genes Are Transcriptionally Repressed by PR in Breast Cancer
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Christy R. Hagan, Geoffrey L. Greene, Victor X. Jin, Katelin A. Gibson, Gloria M. Trinca, Sean M. Holloran, Tianbao Li, Jade A. Hall, Hari Singhal, Merit L. Goodman, and Katherine R. Walter
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The progesterone receptor (PR) regulates transcriptional programs that drive proliferation, survival, and stem cell phenotypes. Although the role of native progesterone in the development of breast cancer remains controversial, PR clearly alters the transcriptome in breast tumors. This study identifies a class of genes, Interferon (IFN)-stimulated genes (ISGs), potently downregulated by ligand-activated PR which have not been previously shown to be regulated by PR. Progestin-dependent transcriptional repression of ISGs was observed in breast cancer cell line models and human breast tumors. Ligand-independent regulation of ISGs was also observed, as basal transcript levels were markedly higher in cells with PR knockdown. PR repressed ISG transcription in response to IFN treatment, the canonical mechanism through which these genes are activated. Liganded PR is robustly recruited to enhancer regions of ISGs, and ISG transcriptional repression is dependent upon PR's ability to bind DNA. In response to PR activation, key regulatory transcription factors that are required for IFN-activated ISG transcription, STAT2 and IRF9, exhibit impaired recruitment to ISG promoter regions, correlating with PR/ligand-dependent ISG transcriptional repression. IFN activation is a critical early step in nascent tumor recognition and destruction through immunosurveillance. As the large majority of breast tumors are PR positive at the time of diagnosis, PR-dependent downregulation of IFN signaling may be a mechanism through which early PR-positive breast tumors evade the immune system and develop into clinically relevant tumors.Implications: This study highlights a novel transcriptional mechanism through which PR drives breast cancer development and potentially evades the immune system. Mol Cancer Res; 15(10); 1331–40. ©2017 AACR. more...
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- 2023
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3. Supplementary Figure from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Supplementary Figure S1 Expression of EpCAM, LEF1 in human endometrial cancer patients, cancer cell lines and mouse endometrial tissues. Supplementary Figure S2 Quantification of EpEX immunofluorescence staining and EGFR expression in endometrial cancer cell lines. Supplementary Figure S3 Summary of ChIP-seq of EpICD in RL95-2 cells. Supplementary Figure S4 Overview of ChIP-seq of LEF1 in RL95-2 cells. Supplementary Figure S5 Pathway enrichment analysis unique/shared TSS-bound genes in 12 and 24 hours EGF. Supplementary Figure S6 105 EpICD-LEF1-TSS gene expression profiles in UCEC (Uterine Corpus Endometrial Carcinoma) patients and normal control samples in TCGA cohort. Supplementary Figure S7 EpCAM-edited cells showed reduced EGF-stimulated gene activation. Supplementary Figure S8 RL95-2 cells showed no apoptosis and cytoskeleton content induced by EGF treatments in RL95-2 and EpCAM-edited clone. Supplementary Figure S9 EpCAM molecules were detected with recognition AFM only on cells expressing this protein. more...
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- 2023
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4. Data from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng more...
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Purpose: We conducted genome-wide miRNA-sequencing (miRNA-seq) in primary cancer tissue from patients of lung adenocarcinoma to identify markers for the presence of lymph node metastasis.Experimental Design: Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using quantitative PCR. After additional validation in the The Cancer Genome Atlas (TCGA) dataset, functional characterization studies were conducted in vitro.Results: MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared with those without lymph node metastases. We confirmed miR-31 to be upregulated in lymph node-positive patients in a separate patient cohort (P = 0.009, t test), and to be expressed at higher levels in adenocarcinoma tissue than in matched normal adjacent lung tissues (P < 0.0001, paired t test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (P = 0.031, t test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling-dependent manner. Notably, miR-31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients.Conclusions: We applied miRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and potentially identified a miRNA predicting the presence of lymph node metastasis and survival outcomes in patients of lung adenocarcinoma. Clin Cancer Res; 19(19); 5423–33. ©2013 AACR. more...
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- 2023
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5. Supplementary Tables from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng more...
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PDF file, 34K, Supplementary Table 1. Clinical demographic information of 43 lung ADC cases. NAT is normal adjacent tissue. Supplementary Table 2. Clinical demographic information of lung adenocarcinoma TCGA patients. Supplementary Table 3. IPA analysis for the downstream targets for miR-31. Supplementary Table 4. Genetic alteration overview of the cell lines used in this study. Supplementary Table 5. Correlation coefficient between EMT-related genes and miR-31 expression. more...
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- 2023
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6. Supplementary Table S2 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Supplementary Table S2: qPCR primer for subcluster E genes
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- 2023
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7. Supplementary Table S1 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Supplementary Table S1: qPCR Primers for androgen responsive genes
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- 2023
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8. Data from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Overexpression of epithelial cell adhesion molecule (EpCAM) has been implicated in advanced endometrial cancer, but its roles in this progression remain to be elucidated. In addition to its structural role in modulating cell-surface adhesion, here we demonstrate that EpCAM is a regulatory molecule in which its internalization into the nucleus turns on a transcription program. Activation of EGF/EGFR signal transduction triggered cell-surface cleavage of EpCAM, leading to nuclear internalization of its cytoplasmic domain EpICD. ChIP-seq analysis identified target genes that are coregulated by EpICD and its transcription partner, LEF-1. Network enrichment analysis further uncovered a group of 105 genes encoding functions for tight junction, adherent, and cell migration. Furthermore, nanomechanical analysis by atomic force microscopy revealed increased softness and decreased adhesiveness of EGF-stimulated cancer cells, implicating acquisition of an epithelial–mesenchymal transition (EMT) phenotype. Thus, genome editing of EpCAM could be associated with altering these nanomechanical properties towards a less aggressive phenotype. Using this integrative genomic–biophysical approach, we demonstrate for the first time an intricate relationship between EpCAM-regulated transcription and altered biophysical properties of cells that promote EMT in advanced endometrial cancer. Cancer Res; 76(21); 6171–82. ©2016 AACR. more...
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- 2023
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9. Supplementary Table S4 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Supplementary Table S4: List of genes most highly associated with each subcluster
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- 2023
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10. Supplementary Figure Legends from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Supplementary Figure Legends Fig S1-S9
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- 2023
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11. Data from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment.Significance: Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen-independent cells that are poised for clonal selection after androgen-deprivation therapy. Cancer Res; 78(4); 853–64. ©2017 AACR. more...
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- 2023
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12. Supplementary Figure S1-10 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Supplementary Figure S1: Time-course expression analysis of LNCaP cells reveals dynamic and heterogeneous responses to androgen stimulation. Supplementary Figure S2: Cell cycle progression of LNCaP cells treated with or without R1881 after cell synchronization by double thymidine block (DTB). Supplementary Figure S3: The summary of aligned and unaligned single-cell RNA-seq reads counts. Supplementary Figure S4: Correlation of single-cell RNA-seq ensemble reads with representative bulk RNA-seq reads. Supplementary Figure S5: Venn diagrams illustrating the comparison of differentially expressed genes found in single- and bulk-cell LNCaP experiments. Supplementary Figure S6: The Mclust algorithm defines likely subgroups using a "model-based" approach. Supplementary Figure S7: Each cell within each subcluster exhibits a similar gene expression profile. Supplementary Figure S8: Gleason score and biochemical recurrence status compared to each subcluster''s gene expression profile. Supplementary Figure S9: Differential expression of 10 genes in LNCaP''s 8.1 subpopulation of cells. Supplementary Figure S10: High single-cell expression of 10 genes in PC3 similar to 12hr-R1881 LNCaP cells. more...
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- 2023
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13. Supplementary Figures from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng more...
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PDF file, 450K, Supplementary Figure 1. The length distribution of reads for ten miR-seq samples Supplementary Figure 2. Flow diagram illustrating microRNA quantification techniques used and sample sizes of each step of the analysis. NAT: normal adjacent tissue. Supplemental Figure 3. Identification of differentially expressed miRNAs between N0 and N1+ groups of patients. Supplementary Figure 4. The receiver operator characteristic (ROC) curve as well as area under curve (AUC) was determined using CART. The results show that AUC is 0.79 in 43 lung ADC samples (cohort 1 +2). Supplementary Figure 5. Higher miR-31 expression is associated with adverse outcome in T2N0 patients (n=75, log-rank p=0.0194) Supplementary Figure 6. IPA showing the top five canonical pathways for miR-31 target genes is the CDK5 (A), PTEN (B), p70S6K (C) , ERK/MAPK (D) and PI3K/AKT (E)signaling. Supplementary Figure 7. Ectopic expression of miR-31 increases migration/invasion capabilities of H2228 cells. (A) Expression of miR-31 following infection with Lenti-miR vector containing miR-31 precursor was confirmed by TaqMan real-time PCR. (B) Cell invasion assay for miR-31 overexpressing H2228 cells. (C) Cell migration assay for miR-31 overexpressing H2228 cells using transwell membranes (upper panel, representative pictures of migration chambers; bottom panel, average counts from 10 random microscopic fields). The average counts were derived from ten random microscopic fields. (D) Cell proliferation assay for miR-31 overexpressing H2228 cells. Data are presented as mean plus-minus S.D. *P more...
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- 2023
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14. Supplementary Material and Methods from EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition
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Tim Hui-Ming Huang, Maria E. Gaczynska, Nameer B. Kirma, Victor X. Jin, Jianhua Ruan, Lu Liu, Yi-Wen Huang, Yao Wang, Pawel Osmulski, and Ya-Ting Hsu
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Transgenic mice,Immunofluorescence staining and image quantification, Proliferation and migration assays, ChIP-seq and network-based pathway analysis, TCGA expression analysis, CRISPR/Cas9 genome-editing of EpCAM, Apoptosis assay, Nanomechanical imaging of cells with Atomic Force Microscopy (AFM), Probing of cell surface with molecular recognition AFM more...
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- 2023
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15. Supplementary Table S5 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Supplementary Table S5: Predictive values of the subcluser E gene panel for biochemical recurrence
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- 2023
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16. Supplementary Table S3 from Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Tim H.-M. Huang, Chun-Liang Chen, Victor X. Jin, Qianben Wang, Wei-Ting Chao, Zhijie Liu, LuZhe Sun, Addanki P. Kumar, Michael A. Liss, Nameer B. Kirma, Chun-Lin Lin, Chiou-Miin Wang, Chia-Nung Hung, Rohit R. Jadhav, Anna D. Louie, Che-Kuang Lin, Yao Wang, and Aaron M. Horning more...
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Supplementary Table S3: P values for significant differences between 0, 6, 12, 24, 36, and 72 hour R1881-treated LNCaP cells
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- 2023
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17. Supplementary Figure Legends from MicroRNA-31 Predicts the Presence of Lymph Node Metastases and Survival in Patients with Lung Adenocarcinoma
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Tim Lautenschlaeger, Victor X. Jin, Arnab Chakravarti, Carlo M. Croce, Patrick Ross, Leona W. Ayers, Sung-Suk Suh, Taewan Kim, Hiroshi Nakanishi, Stefano Volinia, Bin Li, Yao Wang, Alexander Huebner, Vaia Dedousi-Huebner, James Perry, Ri Cui, Zhenqing Ye, and Wei Meng more...
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PDF file, 64K.
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- 2023
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18. Supplementary Figures 1-10, Tables 1-3 from Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
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Yu-Wei Leu, Shu-Huei Hsiao, Tim H.-M. Huang, Kenneth P. Nephew, Long-Bin Jeng, Kuen-daw Tsai, H. Sunny Sun, Chi-Sheng Wu, Yu-Sun Chang, Shaw-Jenq Tsai, Min-Jen Tseng, Victor X. Jin, Kun-Tu Yeh, Pei-Yi Chu, Kuan-Der Lee, Pei-Chi Hou, and I-Wen Teng more...
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Supplementary Figures 1-10, Tables 1-3 from Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
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- 2023
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19. Supplementary Figure 1 from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor
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Paul S. Knoepfler, Peggy J. Farnham, Alice Wey, Jessica M. Lemen, Sheryl R. Krig, Victor X. Jin, and Rebecca Cotterman
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Supplementary Figure 1 from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor
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- 2023
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20. Supplementary Figures 1-6, Tables 1-15, Methods from Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer
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Tim H.-M. Huang, Victor X. Jin, Alfred S. L. Cheng, Huey-Jen L. Lin, Charles L. Shapiro, Bhuvaneswari Ramaswamy, Cenny Taslim, Pei-Yin Hsu, Daniel E. Deatherage, Sandya Liyanarachchi, Yi-Wen Huang, Fei Gu, Rulong Shen, Yu-I Weng, Xun Lan, Ta-Ming Liu, and Tao Zuo more...
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Supplementary Figures 1-6, Tables 1-15, Methods from Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer
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- 2023
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21. Data from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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Tim H-M. Huang, Kenneth P. Nephew, Christoph Plass, Ramana V. Davuluri, Susan H. Wei, Wade V. Welshons, Edward M. Curran, Joseph C. Liu, Victor X. Jin, Meiyun Fan, Pearlly S. Yan, and Yu-Wei Leu
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Alterations in histones, chromatin-related proteins, and DNA methylation contribute to transcriptional silencing in cancer, but the sequence of these molecular events is not well understood. Here we demonstrate that on disruption of estrogen receptor (ER) α signaling by small interfering RNA, polycomb repressors and histone deacetylases are recruited to initiate stable repression of the progesterone receptor (PR) gene, a known ERα target, in breast cancer cells. The event is accompanied by acquired DNA methylation of the PR promoter, leaving a stable mark that can be inherited by cancer cell progeny. Reestablishing ERα signaling alone was not sufficient to reactivate the PR gene; reactivation of the PR gene also requires DNA demethylation. Methylation microarray analysis further showed that progressive DNA methylation occurs in multiple ERα targets in breast cancer genomes. The results imply, for the first time, the significance of epigenetic regulation on ERα target genes, providing new direction for research in this classical signaling pathway. more...
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- 2023
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22. Supplementary Table 1 from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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Tim H-M. Huang, Kenneth P. Nephew, Christoph Plass, Ramana V. Davuluri, Susan H. Wei, Wade V. Welshons, Edward M. Curran, Joseph C. Liu, Victor X. Jin, Meiyun Fan, Pearlly S. Yan, and Yu-Wei Leu
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Supplementary Table 1 from Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer
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- 2023
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23. Data from N-Myc Regulates a Widespread Euchromatic Program in the Human Genome Partially Independent of Its Role as a Classical Transcription Factor
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Paul S. Knoepfler, Peggy J. Farnham, Alice Wey, Jessica M. Lemen, Sheryl R. Krig, Victor X. Jin, and Rebecca Cotterman
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Myc proteins have long been modeled to operate strictly as classic gene-specific transcription factors; however, we find that N-Myc has a robust role in the human genome in regulating global cellular euchromatin, including that of intergenic regions. Strikingly, 90% to 95% of the total genomic euchromatic marks histone H3 acetylated at lysine 9 and methylated at lysine 4 is N-Myc–dependent. However, Myc regulation of transcription, even of genes it directly binds and at which it is required for the maintenance of active chromatin, is generally weak. Thus, Myc has a much more potent ability to regulate large domains of euchromatin than to influence the transcription of individual genes. Overall, Myc regulation of chromatin in the human genome includes both specific genes, but also expansive genomic domains that invoke functions independent of a classic transcription factor. These findings support a new dual model for Myc chromatin function with important implications for the role of Myc in cancer and stem cell biology, including that of induced pluripotent stem cells. [Cancer Res 2008;68(23):9654–62] more...
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- 2023
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24. The splanchnic mesenchyme is the tissue of origin for pancreatic fibroblasts during homeostasis and tumorigenesis
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Lu Han, Yongxia Wu, Kun Fang, Sean Sweeney, Ulyss K. Roesner, Melodie Parrish, Khushbu Patel, Tom Walter, Julia Piermattei, Anthony Trimboli, Julia Lefler, Cynthia D. Timmers, Xue-Zhong Yu, Victor X. Jin, Michael T. Zimmermann, Angela J. Mathison, Raul Urrutia, Michael C. Ostrowski, and Gustavo Leone more...
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Pancreatic Neoplasms ,Mesoderm ,Mice ,Cell Transformation, Neoplastic ,Multidisciplinary ,Carcinogenesis ,Animals ,Homeostasis ,General Physics and Astronomy ,General Chemistry ,Fibroblasts ,Pancreas ,General Biochemistry, Genetics and Molecular Biology - Abstract
Pancreatic cancer is characterized by abundant desmoplasia, a dense stroma composed of extra-cellular and cellular components, with cancer associated fibroblasts (CAFs) being the major cellular component. However, the tissue(s) of origin for CAFs remains controversial. Here we determine the tissue origin of pancreatic CAFs through comprehensive lineage tracing studies in mice. We find that the splanchnic mesenchyme, the fetal cell layer surrounding the endoderm from which the pancreatic epithelium originates, gives rise to the majority of resident fibroblasts in the normal pancreas. In a genetic mouse model of pancreatic cancer, resident fibroblasts expand and constitute the bulk of CAFs. Single cell RNA profiling identifies gene expression signatures that are shared among the fetal splanchnic mesenchyme, adult fibroblasts and CAFs, suggesting a persistent transcriptional program underlies splanchnic lineage differentiation. Together, this study defines the phylogeny of the mesenchymal component of the pancreas and provides insights into pancreatic morphogenesis and tumorigenesis. more...
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- 2023
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25. NucHMM: a method for quantitative modeling of nucleosome organization identifying functional nucleosome states distinctly associated with splicing potentiality
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Victor X. Jin, Tianbao Li, Yufei Huang, and Kun Fang
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Nucleosome organization ,Hidden Markov model ,biology ,Genome, Human ,QH301-705.5 ,RNA Splicing ,Method ,Exons ,Computational biology ,QH426-470 ,Markov Chains ,Human genetics ,Cell Line ,Nucleosomes ,Chromatin ,Exon ,Splicing potentiality ,Histone ,RNA splicing ,biology.protein ,Genetics ,Humans ,Nucleosome ,Biology (General) - Abstract
We develop a novel computational method, NucHMM, to identify functional nucleosome states associated with cell type-specific combinatorial histone marks and nucleosome organization features such as phasing, spacing and positioning. We test it on publicly available MNase-seq and ChIP-seq data in MCF7, H1, and IMR90 cells and identify 11 distinct functional nucleosome states. We demonstrate these nucleosome states are distinctly associated with the splicing potentiality of skipping exons. This advances our understanding of the chromatin function at the nucleosome level and offers insights into the interplay between nucleosome organization and splicing processes. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-021-02465-1. more...
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- 2021
26. Association of adenosine signaling gene signature with estrogen receptor-positive breast and prostate cancer bone metastasis
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Daniel Brian Shropshire, Francisca M. Acosta, Kun Fang, Jaime Benavides, Lu-Zhe Sun, Victor X. Jin, and Jean X. Jiang
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General Medicine - Abstract
Bone metastasis is a common and devastating consequence of several major cancer types, including breast and prostate. Osteocytes are the predominant bone cell, and through connexin (Cx) 43 hemichannels release ATP to the bone microenvironment that can be hydrolyzed to adenosine. Here, we investigated how genes related to ATP paracrine signaling are involved in two common bone-metastasizing malignancies, estrogen receptor positive (ER+) breast and prostate cancers. Compared to other sites, bone metastases of both cancer types expressed higher levels of ENTPD1 and NT5E, which encode CD39 and CD73, respectively, and hydrolyze ATP to adenosine. ADORA3, encoding the adenosine A3 receptor, had a similar expression pattern. In primary ER+ breast cancer, high levels of the triplet ENTPD1/NT5E/ADORA3 expression signature was correlated with lower overall, distant metastasis-free, and progression-free survival. In ER+ bone metastasis biopsies, this expression signature is associated with lower survival. This expression signature was also higher in bone-metastasizing primary prostate cancers than in those that caused other tumor events or did not lead to progressive disease. In 3D culture, a non-hydrolyzable ATP analog inhibited the growth of breast and prostate cancer cell lines more than ATP did. A3 inhibition also reduced spheroid growth. Large-scale screens by the Drug Repurposing Hub found ER+ breast cancer cell lines were uniquely sensitive to adenosine receptor antagonists. Together, these data suggest a vital role for extracellular ATP degradation and adenosine receptor signaling in cancer bone metastasis, and this study provides potential diagnostic means for bone metastasis and specific targets for treatment and prevention. more...
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- 2022
27. Dynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model
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Tianbao Li, Qi Liu, Zhong Chen, Kun Fang, Furong Huang, Xueqi Fu, Qianben Wang, and Victor X. Jin
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GATA2 Transcription Factor ,Male ,Multidisciplinary ,Receptors, Androgen ,Androgens ,Prostate ,Humans ,Prostatic Neoplasms ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Nucleosomes ,Signal Transduction - Abstract
Knowledge gaps remain on how nucleosome organization and dynamic reorganization are governed by specific pioneer factors in a genome-wide manner. In this study, we generate over three billons of multi-omics sequencing data to exploit dynamic nucleosome landscape governed by pioneer factors (PFs), FOXA1 and GATA2. We quantitatively define nine functional nucleosome states each with specific characteristic nucleosome footprints in LNCaP prostate cancer cells. Interestingly, we observe dynamic switches among nucleosome states upon androgen stimulation, accompanied by distinct differential (gained or lost) binding of FOXA1, GATA2, H1 as well as many other coregulators. Intriguingly, we reveal a noncanonical pioneer model of GATA2 that it initially functions as a PF binding at the edge of a nucleosome in an inaccessible crowding array. Upon androgen stimulation, GATA2 re-configures an inaccessible to accessible nucleosome state and subsequently acts as a master transcription factor either directly or recruits signaling specific transcription factors to enhance WNT signaling in an androgen receptor (AR)-independent manner. Our data elicit a pioneer and master dual role of GATA2 in mediating nucleosome dynamics and enhancing downstream signaling pathways. Our work offers structural and mechanistic insight into the dynamics of pioneer factors governing nucleosome reorganization. more...
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- 2022
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28. Haploinsufficiency of a Circadian Clock Gene
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Rubal, Singla, Abhishek, Mishra, Hao, Lin, Ethan, Lorsung, Nam, Le, Su, Tin, Victor X, Jin, and Ruifeng, Cao
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Mice, Knockout ,Mice ,Phenotype ,Circadian Clocks ,Maternal Deprivation ,TOR Serine-Threonine Kinases ,ARNTL Transcription Factors ,Animals ,Brain ,CLOCK Proteins ,Haploinsufficiency ,Autistic Disorder ,Circadian Rhythm - Abstract
Approximately 50-80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene more...
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- 2022
29. Phosphorylated MED1 links transcription recycling and cancer growth
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Zhong Chen, Zhenqing Ye, Raymond E Soccio, Tomoyoshi Nakadai, William Hankey, Yue Zhao, Furong Huang, Fuwen Yuan, Hongyan Wang, Zhifen Cui, Benjamin Sunkel, Dayong Wu, Richard K Dzeng, Jennifer M Thomas-Ahner, Tim H M Huang, Steven K Clinton, Jiaoti Huang, Mitchell A Lazar, Victor X Jin, Robert G Roeder, and Qianben Wang more...
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Male ,Mammals ,Mediator Complex Subunit 1 ,Mediator Complex ,Transcription, Genetic ,Neoplasms ,Genetics ,Animals ,Humans ,RNA Polymerase II ,Phosphorylation - Abstract
Mediator activates RNA polymerase II (Pol II) function during transcription, but it remains unclear whether Mediator is able to travel with Pol II and regulate Pol II transcription beyond the initiation and early elongation steps. By using in vitro and in vivo transcription recycling assays, we find that human Mediator 1 (MED1), when phosphorylated at the mammal-specific threonine 1032 by cyclin-dependent kinase 9 (CDK9), dynamically moves along with Pol II throughout the transcribed genes to drive Pol II recycling after the initial round of transcription. Mechanistically, MED31 mediates the recycling of phosphorylated MED1 and Pol II, enhancing mRNA output during the transcription recycling process. Importantly, MED1 phosphorylation increases during prostate cancer progression to the lethal phase, and pharmacological inhibition of CDK9 decreases prostate tumor growth by decreasing MED1 phosphorylation and Pol II recycling. Our results reveal a novel role of MED1 in Pol II transcription and identify phosphorylated MED1 as a targetable driver of dysregulated Pol II recycling in cancer. more...
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- 2022
30. Autistic-like behavior and cerebellar dysfunction in Bmal1 mutant mice ameliorated by mTORC1 inhibition
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Dong Liu, Carmen Nanclares, Konstanze Simbriger, Kun Fang, Ethan Lorsung, Nam Le, Inês Silva Amorim, Kleanthi Chalkiadaki, Salil Saurav Pathak, Jin Li, Jonathan C. Gewirtz, Victor X. Jin, Paulo Kofuji, Alfonso Araque, Harry T. Orr, Christos G. Gkogkas, and Ruifeng Cao more...
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Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Molecular Biology - Abstract
Although circadian and sleep disorders are frequently associated with autism spectrum disorders (ASD), it remains elusive whether clock gene disruption can lead to autistic-like phenotypes in animals. The essential clock gene Bmal1 has been associated with human sociability and its missense mutations are identified in ASD. Here we report that global Bmal1 deletion led to significant social impairments, excessive stereotyped and repetitive behaviors, as well as motor learning disabilities in mice, all of which resemble core behavioral deficits in ASD. Furthermore, aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 knockout (KO) mice. Electrophysiological recordings uncovered enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in the PCs of Bmal1 KO mice. Differential expression of ASD- and ataxia-associated genes (Ntng2, Mfrp, Nr4a2, Thbs1, Atxn1, and Atxn3) and dysregulated pathways of translational control, including hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling, were identified in the cerebellum of Bmal1 KO mice. Interestingly, the antidiabetic drug metformin reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice. Importantly, conditional Bmal1 deletion only in cerebellar PCs was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in Bmal1 KO mice. Together, these results unveil a previously unidentified role for Bmal1 disruption in cerebellar dysfunction and autistic-like behaviors. Our findings provide experimental evidence supporting a putative role for dysregulation of circadian clock gene expression in the pathogenesis of ASD. more...
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- 2022
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31. Mapping nucleosome and chromatin architectures: A survey of computational methods
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Kun Fang, Junbai Wang, Lu Liu, and Victor X. Jin
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Structural Biology ,Genetics ,Biophysics ,Biochemistry ,Computer Science Applications ,Biotechnology - Abstract
With ever-growing genomic sequencing data, the data variabilities and the underlying biases of the sequencing technologies pose significant computational challenges ranging from the need for accurately detecting the nucleosome positioning or chromatin interaction to the need for developing normalization methods to eliminate systematic biases. This review mainly surveys the computational methods for mapping the higher-resolution nucleosome and higher-order chromatin architectures. While a detailed discussion of the underlying algorithms is beyond the scope of our survey, we have discussed the methods and tools that can detect the nucleosomes in the genome, then demonstrated the computational methods for identifying 3D chromatin domains and interactions. We further illustrated computational approaches for integrating multi-omics data with Hi-C data and the advance of single-cell (sc)Hi-C data analysis. Our survey provides a comprehensive and valuable resource for biomedical scientists interested in studying nucleosome organization and chromatin structures as well as for computational scientists who are interested in improving upon them. more...
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- 2022
32. abc4pwm: affinity based clustering for position weight matrices in applications of DNA sequence analysis
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Omer Ali, Amna Farooq, Mingyi Yang, Victor X. Jin, Magnar Bjørås, and Junbai Wang
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Binding Sites ,Applied Mathematics ,Sequence Analysis, DNA ,Biochemistry ,Computer Science Applications ,Structural Biology ,Chromatin Immunoprecipitation Sequencing ,Cluster Analysis ,Humans ,Position-Specific Scoring Matrices ,Nucleotide Motifs ,Molecular Biology ,Protein Binding ,Transcription Factors - Abstract
Background Transcription factor (TF) binding motifs are identified by high throughput sequencing technologies as means to capture Protein-DNA interactions. These motifs are often represented by consensus sequences in form of position weight matrices (PWMs). With ever-increasing pool of TF binding motifs from multiple sources, redundancy issues are difficult to avoid, especially when every source maintains its own database for collection. One solution can be to cluster biologically relevant or similar PWMs, whether coming from experimental detection or in silico predictions. However, there is a lack of efficient tools to cluster PWMs. Assessing quality of PWM clusters is yet another challenge. Therefore, new methods and tools are required to efficiently cluster PWMs and assess quality of clusters. Results A new Python package Affinity Based Clustering for Position Weight Matrices (abc4pwm) was developed. It efficiently clustered PWMs from multiple sources with or without using DNA-Binding Domain (DBD) information, generated a representative motif for each cluster, evaluated the clustering quality automatically, and filtered out incorrectly clustered PWMs. Additionally, it was able to update human DBD family database automatically, classified known human TF PWMs to the respective DBD family, and performed TF motif searching and motif discovery by a new ensemble learning approach. Conclusion This work demonstrates applications of abc4pwm in the DNA sequence analysis for various high throughput sequencing data using ~ 1770 human TF PWMs. It recovered known TF motifs at gene promoters based on gene expression profiles (RNA-seq) and identified true TF binding targets for motifs predicted from ChIP-seq experiments. Abc4pwm is a useful tool for TF motif searching, clustering, quality assessment and integration in multiple types of sequence data analysis including RNA-seq, ChIP-seq and ATAC-seq. more...
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- 2022
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33. Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection
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Zhifen Cui, Cong Zeng, Furong Huang, Fuwen Yuan, Jingyue Yan, Yue Zhao, Yufan Zhou, William Hankey, Victor X. Jin, Jiaoti Huang, Herman F. Staats, Jeffrey I. Everitt, Gregory D. Sempowski, Hongyan Wang, Yizhou Dong, Shan-Lu Liu, and Qianben Wang more...
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SARS-CoV-2 ,Cathepsin L ,Cell Biology ,Article ,COVID-19 Drug Treatment ,Mice ,Endopeptidases ,Animals ,Cytokines ,Protease Inhibitors ,RNA, Messenger ,Chemokines ,Molecular Biology ,Lung ,Peptide Hydrolases - Abstract
SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR–Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely. We further show that this approach extends survival of mice lethally infected with SARS-CoV-2, correlating with decreased lung virus burden, reduced expression of proinflammatory cytokines/chemokines and diminished severity of pulmonary interstitial inflammation. Postinfection treatment by this nanosystem dramatically lowers the lung virus burden and alleviates virus-induced pathological changes. Our results indicate that targeting lung protease mRNA by Cas13d nanosystem represents a unique strategy for controlling SARS-CoV-2 infection and demonstrate that CRISPR can be used as a potential treatment for SARS-CoV-2 infection. more...
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- 2022
34. Hi-C profiling of cancer spheroids identifies 3D-growth-specific chromatin interactions in breast cancer endocrine resistance
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Lavanya Choppavarapu, Junbai Wang, Kun Fang, Ke Yang, Ruifeng Cao, Jingwei Li, Ismail Jatoi, Victor X. Jin, and Yini Yang
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Adult ,In silico ,Breast Neoplasms ,Endocrine Disruptors ,Biology ,Tamoxifen-resistant breast cancer ,Breast cancer ,Hi-C ,Spheroids, Cellular ,Genetics ,medicine ,Humans ,3D spheroids ,Molecular Biology ,Gene ,Genetics (clinical) ,Research ,Spheroid ,Cancer ,DNA Methylation ,Middle Aged ,medicine.disease ,Chromatin ,Human genetics ,In vitro ,Organoids ,Looping genes ,Cancer research ,Female ,Developmental Biology - Abstract
Background Organoids or spheroids have emerged as a physiologically relevant in vitro preclinical model to study patient-specific diseases. A recent study used spheroids of MCF10 cells to model breast cancer progression and identified targetable alterations more similar to those in vivo. Thus, it is practical and essential to explore and characterize the spheroids of the commonly used human breast cancer (BC) cells. Methods In this study, we conducted Hi-C analyses in three-dimensional (3D) spheroids of MCF10A, MCF7 and MCF7TR cells and compared TADs and looping genes with those in 2D monolayers. Furthermore, we performed in silico functional analysis on 3D-growth-specific looping genes and to compare patient outcomes with or without endocrinal therapy. Finally, we performed 3C/RT-qPCR validations in 3D spheroids and 3D-FISH confirmations in organoids of breast cancer patient tissues. Results We found that chromatin structures have experienced drastic changes during the 3D culture growth of BC cells although there is not much change in the quantity of chromatin domains. We also observed that the strengths of looping genes were statistically different between 2D monolayers and 3D spheroids. We further identified novel 3D growth-specific looping genes within Hippo relevant pathways, of which two genes showed potential prognostic values in measuring the outcome of the endocrine treatment. We finally confirmed a few selected genes in Hippo relevant pathways with enhanced looping in organoids of breast cancer patient tissues. Conclusions Hence, our work has provided significant insights into our understanding of 3D-growth-specific chromatin architecture in tamoxifen-resistant breast cancer. Our analyses suggest that the strengthened looping-mediated Hippo relevant pathways may contribute to endocrine therapy resistance in breast cancer patients. more...
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- 2021
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35. HiCImpute: A Bayesian Hierarchical Model for Identifying Structural Zeros and Enhancing Single Cell Hi-C Data
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Victor X. Jin, Chenggong Han, Qing Xie, and Shili Lin
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Spatial Analysis ,Ecology ,Computer science ,Bayesian probability ,Inference ,Sampling (statistics) ,Bayes Theorem ,Data structure ,Chromatin ,Chromosomes ,Cellular and Molecular Neuroscience ,Computational Theory and Mathematics ,Modeling and Simulation ,Data quality ,Genetics ,Cluster Analysis ,Bayesian hierarchical modeling ,Imputation (statistics) ,Cluster analysis ,Molecular Biology ,Algorithm ,Ecology, Evolution, Behavior and Systematics - Abstract
Single cell Hi-C techniques enable one to study cell to cell variability in chromatin interactions. However, single cell Hi-C (scHi-C) data suffer severely from sparsity, that is, the existence of excess zeros due to insufficient sequencing depth. Complicate things further is the fact that not all zeros are created equal, as some are due to loci truly not interacting because of the underlying biological mechanism (structural zeros), whereas others are indeed due to insufficient sequencing depth (sampling zeros), especially for loci that interact infrequently. Differentiating between structural zeros and sampling zeros is important since correct inference would improve downstream analyses such as clustering and discovery of subtypes. Nevertheless, distinguishing between these two types of zeros has received little attention in the single cell Hi-C literature, where the issue of sparsity has been addressed mainly as a data quality improvement problem. To fill this gap, in this paper, we propose HiCImpute, a Bayesian hierarchy model that goes beyond data quality improvement by also identifying observed zeros that are in fact structural zeros. HiCImpute takes spatial dependencies of scHi-C 2D data structure into account while also borrowing information from similar single cells and bulk data, when such are available. Through an extensive set of analyses of synthetic and real data, we demonstrate the ability of HiCImpute for identifying structural zeros with high sensitivity, and for accurate imputation of dropout values in sampling zeros. Downstream analyses using data improved from HiCImpute yielded much more accurate clustering of cell types compared to using observed data or data improved by several comparison methods. Most significantly, HiCImpute-improved data has led to the identification of subtypes within each of the excitatory neuronal cells of L4 and L5 in the prefrontal cortex. more...
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- 2021
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36. Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice
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Rubal Singla, Abhishek Mishra, Hao Lin, Ethan Lorsung, Nam Le, Su Tin, Victor X. Jin, and Ruifeng Cao
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clock gene ,Bmal1 ,mTOR kinase ,autism ,mice ,Inorganic Chemistry ,endocrine system ,mental disorders ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Approximately 50–80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1+/−) reduced the Bmal1 protein levels by ~50–75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, Bmal1+/− mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD. more...
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- 2022
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37. Epigenomics-based identification of oestrogen-regulated long noncoding RNAs in ER+ breast cancer
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Yufan Zhou, Dan Tang, Xinping Xu, Victor X. Jin, Hu Wang, Li Li, Mingjun Bi, Mingqiu Chen, Wei Zhang, Huimin Tao, Wei Yu, Lizhen Chen, Yan Zheng, Zhao Zhang, and Zhijie Liu
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Transcription, Genetic ,Apoptosis ,Breast Neoplasms ,Biology ,Response Elements ,Epigenesis, Genetic ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Er breast cancer ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,skin and connective tissue diseases ,Molecular Biology ,Gene ,030304 developmental biology ,Epigenomics ,0303 health sciences ,Gene Expression Profiling ,Estrogen Receptor alpha ,Computational Biology ,Estrogens ,Cell Biology ,medicine.disease ,Long non-coding RNA ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,Nuclear receptor ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA, Long Noncoding ,Transcriptome ,Signal Transduction ,Research Paper - Abstract
Breast cancer is one of the most prevalent cancers in women worldwide. Through the regulation of many coding and non-coding target genes, oestrogen (E(2) or 17β-oestradiol) and its nuclear receptor ERα play important roles in breast cancer development and progression. Despite the astounding advances in our understanding of oestrogen-regulated coding genes over the past decades, our knowledge on oestrogen-regulated non-coding targets has just begun to expand. Here we leverage epigenomic approaches to systematically analyse oestrogen-regulated long non-coding RNAs (lncRNAs). Similar to the coding targets of ERα, the transcription of oestrogen-regulated lncRNAs correlates with the activation status of ERα enhancers, measured by eRNA production, chromatin accessibility, and the occupancy of the enhancer regulatory components including P300, MED1, and ARID1B. Our 3D chromatin architecture analyses suggest that lncRNAs and their neighbouring E(2)-resonsive coding genes, exemplified by LINC00160 and RUNX1, might be regulated as a 3D structural unit resulted from enhancer-promoter interactions. Finally, we evaluated the expression levels of LINC00160 and RUNX1 in various types of breast cancer and found that their expression positively correlated with the survival rate in ER+ breast cancer patients, implying that the oestrogen-regulated LINC00160 and its neighbouring RUNX1 might represent potential biomarkers for ER+ breast cancers. more...
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- 2020
38. Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer
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Srikanth R. Polusani, Chun Wei Chen, Guangcun Huang, Lu Liu, Nameer B. Kirma, Chiou Miin Wang, Sang Eun Lee, Ya Ting Hsu, Chun Liang Chen, Yufan Zhou, Nicholas D. Lucio, Philip T. Valente, Edward R. Kost, Jianhua Ruan, Maria Gaczynska, Tim H M Huang, David G. Mutch, Irene Aguilera-Barrantes, Eun Yong Shim, Chun-Lin Lin, Bruce J. Nicholson, Pawel A. Osmulski, Yi-Wen Huang, Pearlly S. Yan, Paul J. Goodfellow, Li Ling Lin, and Victor X. Jin more...
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0301 basic medicine ,Cancer Research ,Cell signaling ,Stromal cell ,Endometrial cancer ,Biology ,medicine.disease ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Epigenetic Repression ,DNA methylation ,medicine ,Cancer research ,Stem cell ,Psychological repression - Abstract
Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro coculture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n = 141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap-junction intercellular communication and cell–cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients. Significance: Studies reveal that adipose-derived stem cells in endometrial cancer pathogenesis influence epigenetic repression of gap junction loci, which suggests targeting of gap junction activity as a preventive strategy for obesity-associated endometrial cancer. more...
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- 2019
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39. Author Correction: Temporal dynamic reorganization of 3D chromatin architecture in hormone-induced breast cancer and endocrine resistance
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Yufan Zhou, Gary S. Stein, Junbai Wang, Tian Li, Shili Lin, Seth Frietze, Diana L. Gerrard, Mahitha Rajendran, Andrew J. Fritz, Rachel Schiff, Victor X. Jin, Yini Yang, and Xiaoyong Fu
- Subjects
Multidisciplinary ,business.industry ,Science ,Endocrine resistance ,General Physics and Astronomy ,General Chemistry ,medicine.disease ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Chromatin ,Breast cancer ,Text mining ,Medicine ,lcsh:Q ,lcsh:Science ,business ,Hormone - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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40. Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
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Qi Liu, Steven M. Kornblau, Victor X. Jin, Tianbao Li, and Nick Garza
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0301 basic medicine ,H3K79me2 ,lcsh:QH426-470 ,lcsh:Medicine ,Methylation ,Histones ,03 medical and health sciences ,Exon ,AML ,Cell Line, Tumor ,Neoplasms ,Genetics ,Cluster Analysis ,Humans ,Epigenetics ,Nucleotide Motifs ,Molecular Biology ,Genetics (clinical) ,biology ,Lysine ,Research ,Alternative splicing ,lcsh:R ,Reproducibility of Results ,DOT1L ,Exons ,Histone-Lysine N-Methyltransferase ,Methyltransferases ,Exon skipping ,Chromatin ,Cell biology ,Gene Expression Regulation, Neoplastic ,Alternative Splicing ,lcsh:Genetics ,030104 developmental biology ,Histone ,Gene Ontology ,RNA splicing ,biology.protein ,Molecular Medicine ,RNA Splice Sites - Abstract
Background Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. Methods In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Results Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Conclusions Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism. Electronic supplementary material The online version of this article (10.1186/s13073-018-0538-1) contains supplementary material, which is available to authorized users. more...
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- 2018
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41. Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle–Related Transcription and Attenuated Androgen Response
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Chun-Lin Lin, Michael A. Liss, Wei-Ting Chao, Yao Wang, Chiou Miin Wang, Rohit R. Jadhav, Chia Nung Hung, Addanki P. Kumar, Anna D Louie, Victor X. Jin, Chun Liang Chen, Lu-Zhe Sun, Aaron M. Horning, Che Kuang Lin, Nameer B. Kirma, Tim H M Huang, Qianben Wang, and Zhijie Liu more...
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Male ,0301 basic medicine ,Cancer Research ,medicine.drug_class ,Cell ,Biology ,Article ,03 medical and health sciences ,Prostate cancer ,Cell Line, Tumor ,LNCaP ,medicine ,Humans ,Mitosis ,Gene Expression Profiling ,CENPF ,Prostatic Neoplasms ,Cell cycle ,medicine.disease ,Androgen ,Androgen receptor ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Androgens ,Cancer research ,biology.protein ,RNA - Abstract
Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment. Significance: Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen-independent cells that are poised for clonal selection after androgen-deprivation therapy. Cancer Res; 78(4); 853–64. ©2017 AACR. more...
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- 2018
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42. Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice
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Salil Saurav Pathak, Yi Mei Yang, Bowen Yang, Ruifeng Cao, Dong Liu, Jin Li, Ramanujam Karthikeyan, Victor X. Jin, Owen Y. Chao, and Kun Fang
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circadian rhythm ,Aging ,Dendritic spine ,Light ,Transcription, Genetic ,MAP Kinase Signaling System ,QH301-705.5 ,Dendritic Spines ,Photoperiod ,autism ,Motor Activity ,Hippocampal formation ,Biology ,Neurotransmission ,Inhibitory postsynaptic potential ,Hippocampus ,Synaptic Transmission ,Article ,Biological Clocks ,Risk Factors ,Animals ,Hippocampus (mythology) ,Circadian rhythm ,Autistic Disorder ,Biology (General) ,PI3K/AKT/mTOR pathway ,Genome ,Behavior, Animal ,Suprachiasmatic nucleus ,Gene Expression Profiling ,TOR Serine-Threonine Kinases ,Brain ,translational control ,General Medicine ,neurodevelopmental disorder ,MAPK ,Mice, Inbred C57BL ,mTOR ,Gene Expression Regulation ,Protein Biosynthesis ,Neuroscience - Abstract
Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the “Short Day” (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment. more...
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- 2021
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43. Integration of DNA methylation and gene transcription across nineteen cell types reveals cell type-specific and genomic region-dependent regulatory patterns
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Yufan Zhou, Tim H M Huang, Chiou Miin Wang, Victor X. Jin, and Binhua Tang
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0301 basic medicine ,Transcription, Genetic ,Science ,Biology ,Regulatory Sequences, Nucleic Acid ,Article ,Cell Line ,03 medical and health sciences ,Epigenetics of physical exercise ,Cell Line, Tumor ,Humans ,RNA-Directed DNA Methylation ,Epigenomics ,Regulation of gene expression ,Genetics ,Multidisciplinary ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Methylation ,Genomics ,DNA Methylation ,030104 developmental biology ,Differentially methylated regions ,Gene Expression Regulation ,Organ Specificity ,DNA methylation ,Illumina Methylation Assay ,Medicine ,CpG Islands - Abstract
Despite numerous studies done on understanding the role of DNA methylation, limited work has focused on systems integration of cell type-specific interplay between DNA methylation and gene transcription. Through a genome-wide analysis of DNA methylation across 19 cell types with T-47D as reference, we identified 106,252 cell type-specific differentially-methylated CpGs categorized into 7,537 differentially (46.6% hyper- and 53.4% hypo-) methylated regions. We found 44% promoter regions and 75% CpG islands were T-47D cell type-specific methylated. Pyrosequencing experiments validated the cell type-specific methylation across three benchmark cell lines. Interestingly, these DMRs overlapped with 1,145 known tumor suppressor genes. We then developed a Bayesian Gaussian Regression model to measure the relationship among DNA methylation, genomic segment distribution, differential gene expression and tumor suppressor gene status. The model uncovered that 3′UTR methylation has much less impact on transcriptional activity than other regions. Integration of DNA methylation and 82 transcription factor binding information across the 19 cell types suggested diverse interplay patterns between the two regulators. Our integrative analysis reveals cell type-specific and genomic region-dependent regulatory patterns and provides a perspective for integrating hundreds of various omics-seq data together. more...
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- 2017
44. Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion
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Christine A. Brantner, Yufan Zhou, Xiaowen Zhang, Anastas Popratiloff, Zhiqiang An, Hui Deng, Debarati Banik, Deborah L. Berry, Payal Mitra, Madeleine Prevost, Claudine Isaacs, Victor X. Jin, Eline Blommaert, Aaron M. Rozeboom, Xiujie Sun, Antonio Gomez, Junquan Liu, Yanfen Hu, Roderic Espin Garcia, Wei Xiong, Tyler J. Curiel, Rong Li, Brent T. Harris, Bogang Wu, Deyi Zhang, Miguel Angel Pujana, Krysta Chaldekas, Catherine Lai, Huai-Chin Chiang, Patricia S. Latham, and Ningyan Zhang more...
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T-Lymphocytes ,Triple Negative Breast Neoplasms ,Collagen receptor ,Extracellular matrix ,Gene Knockout Techniques ,Mice ,Immune system ,Discoidin Domain Receptor 1 ,Cell Line, Tumor ,Extracellular ,Animals ,Humans ,DDR1 ,Multidisciplinary ,biology ,Chemistry ,Extracellular Matrix ,Disease Models, Animal ,biology.protein ,Cancer research ,Female ,Tumor Escape ,Collagen ,Immunotherapy ,Antibody ,Tyrosine kinase ,Immunocompetence ,Discoidin domain ,Gene Deletion - Abstract
Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM. In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration. more...
- Published
- 2019
45. Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance
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Victor X. Jin, Mingjun Bi, Karen Hernandez, Qianben Wang, Christopher K. Glass, Wei Li, Hu Wang, Pengya Xue, Jianhua Ruan, Zhao Zhang, Rachel Schiff, Xiaoyong Fu, Lizhen Chen, Carmine De Angelis, Tim H M Huang, Zhijie Liu, Elisabetta Marangoni, and Zhen Gao more...
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AP-1 transcription factor ,Phenotypic plasticity ,Downregulation and upregulation ,GATA3 ,medicine ,Cancer ,Biology ,Enhancer ,medicine.disease ,Reprogramming ,Transcription factor ,Cell biology - Abstract
Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression. more...
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- 2019
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46. Disruption of Broad Epigenetic Domains in PDAC Cells by HAT Inhibitors
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Joseph R. Boyd, Diana L. Gerrard, Gary S. Stein, Victor X. Jin, and Seth Frietze
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0301 basic medicine ,Cell type ,Health, Toxicology and Mutagenesis ,pancreatic cancer ,lcsh:Medicine ,Computational biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Genetics ,medicine ,Epigenetics ,lcsh:QH301-705.5 ,Epigenomics ,biology ,lcsh:R ,super-enhancers ,Histone acetyltransferase ,medicine.disease ,Phenotype ,030104 developmental biology ,Histone ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,epigenomics ,biology.protein ,H3K4me3 - Abstract
The spreading of epigenetic domains has emerged as a distinguishing epigenomic phenotype for diverse cell types. In particular, clusters of H3K27ac- and H3K4me3-marked elements, referred to as super-enhancers, and broad H3K4me3 domains, respectively, have been linked to cell identity and disease states. Here, we characterized the broad domains from different pancreatic ductal adenocarcinoma (PDAC) cell lines that represent distinct histological grades. Our integrative genomic analysis found that human derived cell line models for distinct PDAC grades exhibit characteristic broad epigenetic features associated with gene expression patterns that are predictive of patient prognosis and provide insight into pancreatic cancer cell identity. In particular, we find that genes marked by overlapping Low-Grade broad domains correspond to an epithelial phenotype and hold potential as markers for patient stratification. We further utilize ChIP-seq to compare the effects of histone acetyltransferase (HAT) inhibitors to detect global changes in histone acetylation and methylation levels. We found that HAT inhibitors impact certain broad domains of pancreatic cancer cells. Overall, our results reveal potential roles for broad domains in cells from distinct PDAC grades and demonstrate the plasticity of particular broad epigenomic domains to epigenetic inhibitors. more...
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- 2019
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47. Progesterone Receptor Attenuates STAT1-Mediated IFN Signaling in Breast Cancer
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Zhao Lai, Prabhakar Chalise, Rashna Madan, Evangelia K. Papachristou, Mary A. Markiewicz, Qi Liu, Fang Fan, Gloria M. Trinca, Tianbao Li, Merit L. Goodman, Victor X. Jin, Katherine R. Walter, Clive D'Santos, Jason S. Carroll, Christy R. Hagan, Carroll, Jason [0000-0003-3643-0080], and Apollo - University of Cambridge Repository more...
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Immunology ,Breast Neoplasms ,Biology ,Article ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Breast cancer ,Immune system ,Downregulation and upregulation ,Cell Line, Tumor ,Progesterone receptor ,medicine ,Immunology and Allergy ,Humans ,STAT1 ,Phosphorylation ,Receptor ,Transcription factor ,Promoter ,medicine.disease ,Neoplasm Proteins ,STAT1 Transcription Factor ,biology.protein ,Cancer research ,Female ,Tumor Escape ,Receptors, Progesterone ,030215 immunology - Abstract
Why some tumors remain indolent and others progress to clinical relevance remains a major unanswered question in cancer biology. IFN signaling in nascent tumors, mediated by STAT1, is a critical step through which the surveilling immune system can recognize and destroy developing tumors. In this study, we have identified an interaction between the progesterone receptor (PR) and STAT1 in breast cancer cells. This interaction inhibited efficient IFN-induced STAT1 phosphorylation, as we observed a decrease in phospho-STAT1 in response to IFN treatment in PR-positive breast cancer cell lines. This phenotype was further potentiated in the presence of PR ligand. In human breast cancer samples, PR-positive tumors exhibited lower levels of phospho-STAT1 as compared with their PR-negative counterparts, indicating that this phenotype translates to human tumors. Breast cancer cells lacking PR exhibited higher levels of IFN-stimulated gene (ISG) RNA, the transcriptional end point of IFN activation, indicating that unliganded PR alone could decrease transcription of ISGs. Moreover, the absence of PR led to increased recruitment of STAT1, STAT2, and IRF9 (key transcription factors necessary for ISG transcription) to ISG promoters. These data indicate that PR, both in the presence and absence of ligand, attenuates IFN-induced STAT1 signaling, culminating in significantly abrogated activation of genes transcribed in response to IFNs. PR-positive tumors may use downregulation of STAT1-mediated IFN signaling to escape immune surveillance, leading to the development of clinically relevant tumors. Selective immune evasion of PR-positive tumors may be one explanation as to why over 65% of breast cancers are PR positive at the time of diagnosis., This work was supported by the National Cancer Institute (NCI) R00CA166643 (to C.R.H.), Department of Defense Breast Cancer Research Program W81XWH-16-1-0320 (to C.R.H.), Susan G. Komen Foundation CCR16376147 (to C.R.H.), V Foundation V2015-025 (to C.R.H.), National Institutes of Health R01GM114142 (to V.X.J.), U54CA217297 (to V.X.J.), and 1S10OD021805-01 (to Z.L.), the Owens Foundation (to V.X.J.), and NCI Cancer Center Support Grant P30 CA168524 (to C.R.H.). more...
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- 2019
48. Enhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance
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Carmine De Angelis, Victor X. Jin, Zhi Ming Shao, Christopher K. Glass, Hu Wang, Jianhua Ruan, Lizhen Chen, Yue Gong, Pengya Xue, Zhao Zhang, Tim H M Huang, Zhijie Liu, Zhen Gao, Yi-Zhou Jiang, Zhao Lai, Wei Li, Rachel Schiff, Xiaoyong Fu, Mingjun Bi, Elisabetta Marangoni, Elodie Montaudon, Bi, M., Zhang, Z., Jiang, Y. -Z., Xue, P., Wang, H., Lai, Z., Fu, X., De Angelis, C., Gong, Y., Gao, Z., Ruan, J., Jin, V. X., Marangoni, E., Montaudon, E., Glass, C. K., Li, W., Huang, T. H. -M., Shao, Z. -M., Schiff, R., Chen, L., and Liu, Z. more...
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Transcriptional Activation ,Xenograft Model Antitumor Assay ,Antineoplastic Agents, Hormonal ,Mice, Nude ,Apoptosis ,Breast Neoplasms ,GATA3 Transcription Factor ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Enhancer ,Transcription factor ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Animal ,GATA3 ,Estrogen Receptor alpha ,Apoptosi ,Cancer ,Cell Biology ,medicine.disease ,Cellular Reprogramming ,Adaptation, Physiological ,Xenograft Model Antitumor Assays ,Cell biology ,Gene Expression Regulation, Neoplastic ,Transcription Factor AP-1 ,AP-1 transcription factor ,Tamoxifen ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Reprogramming ,Breast Neoplasm ,Human - Abstract
Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance. more...
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- 2019
49. BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells
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Ben Ho Park, Yanfen Hu, Huai-Chin Chiang, Chang Lu, Victor X. Jin, Yao Wang, Yuan-Pang Hsieh, Xiaowen Zhang, Rong Li, and Ismail Jatoi
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Genome instability ,Chromatin Immunoprecipitation ,endocrine system diseases ,Genes, BRCA1 ,Haploinsufficiency ,medicine.disease_cause ,lcsh:RC254-282 ,Genomic Instability ,Cell Line ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Transcriptional regulation ,Humans ,Breast epithelial cells ,Epigenetics ,Nucleotide Motifs ,Mammary Glands, Human ,skin and connective tissue diseases ,Enhancer ,Binding Sites ,biology ,Chemistry ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Epithelial Cells ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,BRCA1 ,Chromatin ,Super-enhancer ,3. Good health ,Cell biology ,Chromatin looping ,Cell Transformation, Neoplastic ,Enhancer Elements, Genetic ,Histone ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Carcinogenesis ,Transcription ,Protein Binding ,Research Article - Abstract
Background BRCA1-associated breast cancer originates from luminal progenitor cells. BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. While non-malignant cells carrying cancer-predisposing BRCA1 mutations exhibit increased genomic instability, it remains unclear whether BRCA1 haploinsufficiency affects transcription and chromatin dynamics in breast epithelial cells. Methods H3K27ac-associated super-enhancers were compared in primary breast epithelial cells from BRCA1 mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+). Non-tumorigenic MCF10A breast epithelial cells with engineered BRCA1 haploinsufficiency were used to confirm the H3K27ac changes. The impact of BRCA1 mutations on enhancer function and enhancer-promoter looping was assessed in MCF10A cells. Results Here, we show that primary mammary epithelial cells from women with BRCA1 mutations display significant loss of H3K27ac-associated super-enhancers. These BRCA1-dependent super-enhancers are enriched with binding motifs for the GATA family. Non-tumorigenic BRCA1mut/+ MCF10A cells recapitulate the H3K27ac loss. Attenuated histone mark and enhancer activity in these BRCA1mut/+ MCF10A cells can be partially restored with wild-type BRCA1. Furthermore, chromatin conformation analysis demonstrates impaired enhancer-promoter looping in BRCA1mut/+ MCF10A cells. Conclusions H3K27ac-associated super-enhancer loss is a previously unappreciated functional deficiency in ostensibly normal BRCA1 mutation-carrying breast epithelium. Our findings offer new mechanistic insights into BRCA1 mutation-associated transcriptional and epigenetic abnormality in breast epithelial cells and tissue/cell lineage-specific tumorigenesis. Electronic supplementary material The online version of this article (10.1186/s13058-019-1132-1) contains supplementary material, which is available to authorized users. more...
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- 2019
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50. COPAR: A ChIP-Seq Optimal Peak Analyzer
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Xihan Wang, Victor X. Jin, and Binhua Tang
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0301 basic medicine ,Spectrum analyzer ,Article Subject ,Computer science ,Reliability (computer networking) ,0206 medical engineering ,Feature extraction ,Sequencing data ,lcsh:Medicine ,02 engineering and technology ,Bioinformatics ,computer.software_genre ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Software ,Humans ,Genome ,General Immunology and Microbiology ,business.industry ,Design of experiments ,lcsh:R ,Process (computing) ,High-Throughput Nucleotide Sequencing ,Genomics ,Sequence Analysis, DNA ,General Medicine ,Chip ,030104 developmental biology ,Data mining ,business ,computer ,020602 bioinformatics ,Research Article - Abstract
Sequencing data quality and peak alignment efficiency of ChIP-sequencing profiles are directly related to the reliability and reproducibility of NGS experiments. Till now, there is no tool specifically designed for optimal peak alignment estimation and quality-related genomic feature extraction for ChIP-sequencing profiles. We developed open-sourced COPAR, a user-friendly package, to statistically investigate, quantify, and visualize the optimal peak alignment and inherent genomic features using ChIP-seq data from NGS experiments. It provides a versatile perspective for biologists to perform quality-check for high-throughput experiments and optimize their experiment design. The package COPAR can process mapped ChIP-seq read file in BED format and output statistically sound results for multiple high-throughput experiments. Together with three public ChIP-seq data sets verified with the developed package, we have deposited COPAR on GitHub under a GNU GPL license. more...
- Published
- 2017
- Full Text
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