84 results on '"Flemington, Erik K."'
Search Results
2. Transcriptional signatures of Zika virus infection in astrocytes
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Schouest, Blake, Peterson, Tiffany A., Szeltner, Dawn M., Scheef, Elizabeth A., Baddoo, Melody, Ungerleider, Nathan, Flemington, Erik K., MacLean, Andrew G., and Maness, Nicholas J.
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- 2021
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3. High-density resolution of the Kaposi's sarcoma associated herpesvirus transcriptome identifies novel transcript isoforms generated by long-range transcription and alternative splicing.
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Shekhar, Ritu, O'Grady, Tina, Keil, Netanya, Feswick, April, Amador, David A Moraga, Tibbetts, Scott A, Flemington, Erik K, and Renne, Rolf
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- 2024
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4. Viral reprogramming of host transcription initiation.
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Ungerleider, Nathan A, Roberts, Claire, O'Grady, Tina M, Nguyen, Trang T, Baddoo, Melody, Wang, Jia, Ishaq, Eman, Concha, Monica, Lam, Meggie, Bass, Jordan, Nguyen, Truong D, Van Otterloo, Nick, Wickramarachchige-Dona, Nadeeshika, Wyczechowska, Dorota, Morales, Maria, Ma, Tianfang, Dong, Yan, and Flemington, Erik K
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- 2024
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5. SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
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Kim, Jung-Hyun, Jeong, Kyuho, Li, Jianfeng, Murphy, James M., Vukadin, Lana, Stone, Joshua K., Richard, Alexander, Tran, Johnny, Gillespie, G. Yancey, Flemington, Erik K., Sobol, Robert W., Lim, Ssang-Teak Steve, and Ahn, Eun-Young Erin
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- 2021
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6. Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians
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Yadav, Santosh, Anbalagan, Muralidharan, Baddoo, Melody, Chellamuthu, Vinodh K., Mukhopadhyay, Sudurika, Woods, Carol, Jiang, Wei, Moroz, Krzysztof, Flemington, Erik K, and Makridakis, Nick
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- 2020
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7. Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer
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Cao, Subing, Ma, Tianfang, Ungerleider, Nathan, Roberts, Claire, Kobelski, Margaret, Jin, Lianjin, Concha, Monica, Wang, Xia, Baddoo, Melody, Nguyen, Holly M., Corey, Eva, Fazli, Ladan, Ledet, Elisa, Zhang, Rubin, Silberstein, Jonathan L., Zhang, Wensheng, Zhang, Kun, Sartor, Oliver, Dong, Xuesen, Flemington, Erik K., and Dong, Yan
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- 2019
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8. Connivance, Complicity, or Collusion? The Role of Noncoding RNAs in Promoting Gammaherpesvirus Tumorigenesis
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Bullard, Whitney L., Flemington, Erik K., Renne, Rolf, and Tibbetts, Scott A.
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- 2018
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9. Alterations in gene expression and microbiome composition upon calcium-sensing receptor deletion in the mouse esophagus.
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Abdulnour-Nakhoul, Solange M., Kolls, Jay K., Flemington, Erik K., Ungerleider, Nathan A., Nakhoul, Hani N., Song, Kejing, and Nakhoul, Nazih L.
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CALCIUM-sensing receptors ,GENE expression ,KNOCKOUT mice ,G protein coupled receptors ,TIGHT junctions ,GENE expression profiling ,CELL cycle proteins - Abstract
The calcium-sensing receptor (CaSR), a G protein-coupled receptor, regulates Ca
2+ concentration in plasma by regulating parathyroid hormone secretion. In other tissues, it is reported to play roles in cellular differentiation and migration and in secretion and absorption. We reported previously that CaSR can be conditionally deleted in the mouse esophagus. This conditional knockout (KO) (Eso CaSR-/- ) model showed a significant reduction in the levels of adherens and tight junction proteins and had a marked buildup of bacteria on the luminal esophageal surface. To further examine the role of CaSR, we used RNA sequencing to determine gene expression profiles in esophageal epithelia of control andEso CaSR-/- mice RNA Seq data indicated upregulation of gene sets involved in DNA replication and cell cycle inEso CaSR-/- . This is accompanied by the downregulation of gene sets involved in the innate immune response and protein homeostasis including peptide elongation and protein trafficking. Ingenuity pathway analysis (IPA) demonstrated that these genes are mapped to important biological networks including calcium and Ras homologus A (RhoA) signaling pathways. To further explore the bacterial buildup inEso CaSR-/- esophageal tissue, 16S sequencing of the mucosal-associated bacterial microbiome was performed. Three bacterial species, g_Rodentibacter, s_Rodentibacter_unclassified, and s_Lactobacillus_hilgardi were significantly increased inEso CaSR-/- . Furthermore, metagenomic analysis of 16S sequences indicated that pathways related to oxidative phosphorylation and metabolism were downregulated inEso CaSR-/- tissues. These data demonstrate that CaSR impacts major pathways of cell proliferation, differentiation, cell cycle, and innate immune response in esophageal epithelium. The disruption of these pathways causes inflammation and significant modifications of the microbiome. [ABSTRACT FROM AUTHOR]- Published
- 2024
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10. Transcriptome analysis reveals sexual disparities in gene expression in rat brain microvessels
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Chandra, Partha K, Cikic, Sinisa, Baddoo, Melody C, Rutkai, Ibolya, Guidry, Jessie J, Flemington, Erik K, Katakam, Prasad VG, and Busija, David W
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- 2021
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11. A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer
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Bai, Shanshan, Cao, Subing, Jin, Lianjin, Kobelski, Margaret, Schouest, Blake, Wang, Xiaojie, Ungerleider, Nathan, Baddoo, Melody, Zhang, Wensheng, Corey, Eva, Vessella, Robert L., Dong, Xuesen, Zhang, Kun, Yu, Xianghui, Flemington, Erik K., and Dong, Yan
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- 2019
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12. SEER and Gene Expression Data Analysis Deciphers Racial Disparity Patterns in Prostate Cancer Mortality and the Public Health Implication
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Zhang, Wensheng, Dong, Yan, Sartor, Oliver, Flemington, Erik K., and Zhang, Kun
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- 2020
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13. Assessment of viral RNA in idiopathic pulmonary fibrosis using RNA-seq
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Yin, Qinyan, Strong, Michael J., Zhuang, Yan, Flemington, Erik K., Kaminski, Naftali, de Andrade, Joao A., and Lasky, Joseph A.
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- 2020
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14. Transcriptomic analysis identifies B-lymphocyte kinase as a therapeutic target for desmoplastic small round cell tumor cancer stem cell-like cells.
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Magrath, Justin W., Flinchum, Dane A., Hartono, Alifiani B., Sampath, Shruthi Sanjitha, O'Grady, Tina M., Baddoo, Melody, Haoyang, Liang, Xu, Xiaojiang, Flemington, Erik K., and Lee, Sean B.
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- 2024
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15. Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development
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Dai, Lu, Del Valle, Luis, Miley, Wendell, Whitby, Denise, Ochoa, Augusto C., Flemington, Erik K., and Qin, Zhiqiang
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- 2018
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16. The modularity and dynamicity of miRNA–mRNA interactions in high-grade serous ovarian carcinomas and the prognostic implication
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Zhang, Wensheng, Edwards, Andrea, Fan, Wei, Flemington, Erik K., and Zhang, Kun
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- 2016
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17. Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix
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Li, Miao, Li, Xi, Zhuang, Yan, Flemington, Erik K., Lin, Zhen, and Shan, Bin
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- 2017
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18. Transferring knowledge of bacterial protein interaction networks to predict pathogen targeted human genes and immune signaling pathways: a case study on M. tuberculosis
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Mei, Suyu, Flemington, Erik K., and Zhang, Kun
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- 2018
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19. Reversal of splicing infidelity is a pre-activation step in B cell differentiation.
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O'Grady, Tina M., Baddoo, Melody, Flemington, Samuel A., Ishaq, Eman Y., Ungerleider, Nathan A., and Flemington, Erik K.
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B cell differentiation ,EPSTEIN-Barr virus diseases ,B cells ,LYMPHOID tissue ,CELL communication ,GENE ontology - Abstract
Introduction: B cell activation and differentiation is central to the adaptive immune response. Changes in exon usage can have major impacts on cellular signaling and differentiation but have not been systematically explored in differentiating B cells. Methods: We analyzed exon usage and intron retention in RNA-Seq data from subsets of human B cells at various stages of differentiation, and in an in vitro laboratory model of B cell activation and differentiation (Epstein Barr virus infection). Results: Blood naive B cells were found to have an unusual splicing profile, with unannotated splicing events in over 30% of expressed genes. Splicing changed substantially upon naive B cell entry into secondary lymphoid tissue and before activation, involving significant increases in exon commitment and reductions in intron retention. These changes preferentially involved short introns with weak splice sites and were likely mediated by an overall increase in splicing efficiency induced by the lymphoid environment. The majority of transcripts affected by splicing changes showed restoration of encoded conserved protein domains and/or reduced targeting to the nonsense-mediated decay pathway. Affected genes were enriched in functionally important immune cell activation pathways such as antigen-mediated signaling, cell cycle control and mRNA processing and splicing. Discussion: Functional observations from donor B cell subsets in progressive states of differentiation and from timecourse experiments using the in vitro model suggest that these widespread changes in mRNA splicing play a role in preparing naive B cells for the decisive step of antigen-mediated activation and differentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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20. Establishment and characterization of a new mantle cell lymphoma cell line with a NOTCH2 mutation, Arbo.
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Safa, Firas, Rasmussen, Terri, Lobelle‐Rich, Patricia, Collier, Stephanie, Milligan, Nicholas, Schmeig, John, Schmid, Janet, Wiewiorowski, Carol, Totaro, Denise, Brown, Theresa C., Satyavarapu, Ishwarya, Badoo, Melody, Ungerleider, Nathan, Flemington, Erik K., Safah, Hana, and Saba, Nakhle S.
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- 2022
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21. Elevated Expression of Long Intergenic Non-Coding RNA HOTAIR in a Basal-Like Variant of MCF-7 Breast Cancer Cells
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Zhuang, Yan, Nguyen, Hong T., Burow, Matthew E., Zhuo, Ying, El-Dahr, Samir S., Yao, Xiao, Cao, Subing, Flemington, Erik K., Nephew, Kenneth P., Fang, Fang, Collins-Burow, Bridgette, Rhodes, Lyndsay V., Yu, Qiang, Jayawickramarajah, Janarthanan, and Shan, Bin
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- 2015
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22. Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells
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Strong, Amy L., Shi, Zhenzhen, Strong, Michael J., Miller, David F.B., Rusch, Douglas B., Buechlein, Aaron M., Flemington, Erik K., McLachlan, John A., Nephew, Kenneth P., Burow, Matthew E., and Bunnell, Bruce A.
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Stem cells -- Health aspects ,Cell differentiation -- Health aspects ,DDT (Insecticide) -- Health aspects ,Environmental issues ,Health - Abstract
BACKGROUND: Although the global use of the endocrine-disrupting chemical DDT has decreased, its persistence in the environment has resulted in continued human exposure. Accumulating evidence suggests that DDT exposure has long-term adverse effects on development, yet the impact on growth and differentiation of adult stem cells remains unclear. OBJECTIVES: Human mesenchymal stem cells (MSCs) exposed to DDT were used to evaluate the impact on stem cell biology. METHODS: We assessed DDT-treated MSCs for self-renewal, proliferation, and differentiation potential. Whole genome RNA sequencing was performed to assess gene expression in DDT-treated MSCs. RESULTS: MSCs exposed to DDT formed fewer colonies, suggesting a reduction in self-renewal potential. DDT enhanced both adipogenic and osteogenic differentiation, which was confirmed by increased mRNA expression of glucose transporter type 4 (GLUT4), lipoprotein lipase (LpL), peroxisome proliferator-activated receptor gamma (PPARf), leptin, osteonectin, core binding factor 1 (CBFA1), and FBJ murine osteosarcoma viral oncogene homolog (c-Fos). Expression of factors in DDT-treated cells was similar to that in estrogen-treated MSCs, suggesting that DDT may function via the estrogen receptor (ER)-mediated pathway. The coadministration of ICI 182,780 blocked the effects of DDT. RNA sequencing revealed 121 genes and noncoding RNAs to be differentially expressed in DDT-treated MSCs compared with controls cells. CONCLUSION: Human MSCs provide a powerful biological system to investigate and identify the molecular mechanisms underlying the effects of environmental agents on stem cells and human health. MSCs exposed to DDT demonstrated profound alterations in self-renewal, proliferation, differentiation, and gene expression, which may partially explain the homeostatic imbalance and increased cancer incidence among those exposed to long-term EDCs. CITATION: Strong AL, Shi Z, Strong MJ, Miller DF, Rusch DB, Buechlein AM, Flemington EK, McLachlan JA, Nephew KP, Burow ME, Bunnell BA. 2015. Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells. Environ Health Perspect 123:42-48; http://dx.doi.org/ 10.1289/ehp.1408188, Introduction Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds capable of altering hormonal and homeostatic systems. Although factors such as age, duration, EDC type, and dose-response dynamics influence the severity [...]
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- 2015
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23. EBV miRNAs are potent effectors of tumor cell transcriptome remodeling in promoting immune escape.
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Ungerleider, Nathan, Bullard, Whitney, Kara, Mehmet, Wang, Xia, Roberts, Claire, Renne, Rolf, Tibbetts, Scott, and Flemington, Erik K.
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KAPOSI'S sarcoma-associated herpesvirus ,MICRORNA ,BURKITT'S lymphoma ,ONCOGENIC DNA viruses ,NON-coding RNA - Abstract
The Epstein Barr virus (EBV) contributes to the tumor phenotype through a limited set of primarily non-coding viral RNAs, including 31 mature miRNAs. Here we investigated the impact of EBV miRNAs on remodeling the tumor cell transcriptome. Strikingly, EBV miRNAs displayed exceptionally abundant expression in primary EBV-associated Burkitt's Lymphomas (BLs) and Gastric Carcinomas (GCs). To investigate viral miRNA targeting, we used the high-resolution approach, CLASH in GC and BL cell models. Affinity constant calculations of targeting efficacies for CLASH hits showed that viral miRNAs bind their targets more effectively than their host counterparts, as did Kaposi's sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68) miRNAs. Using public BL and GC RNA-seq datasets, we found that high EBV miRNA targeting efficacies translates to enhanced reduction of target expression. Pathway analysis of high efficacy EBV miRNA targets showed enrichment for innate and adaptive immune responses. Inhibition of the immune response by EBV miRNAs was functionally validated in vivo through the finding of inverse correlations between EBV miRNAs and immune cell infiltration and T-cell diversity in BL and GC datasets. Together, this study demonstrates that EBV miRNAs are potent effectors of the tumor transcriptome that play a role in suppressing host immune response. Author summary: Burkitt's Lymphoma and gastric cancer are both associated with EBV, a prolific DNA tumor virus that latently resides in nearly all human beings. Despite mostly restricting viral gene expression to noncoding RNAs, EBV has important influences on the fitness of infected tumor cells. Here, we show that the miRNA class of viral noncoding RNAs are a major viral contributor to remodeling the tumor cell regulatory machinery in patient tumor samples. First, an assessment of miRNA expression in clinical tumor samples showed that EBV miRNAs are expressed at unexpectedly high levels relative to cell miRNAs. Using a highly specific miRNA target identification approach, CLASH, we comprehensively identified both viral and cellular miRNA targets and the relative abundance of each miRNA-mRNA interaction. We also show that viral miRNAs bind to and alter the expression of their mRNA targets more effectively than their cellular miRNA counterparts. Pathway analysis of the most effectively targeted mRNAs revealed enrichment of immune signaling pathways and we show a corresponding inverse correlation between EBV miRNA expression and infiltrating immune cells in EBV positive primary tumors. Altogether, this study shows that EBV miRNAs are key regulators of the tumor cell phenotype and the immune cell microenvironment. [ABSTRACT FROM AUTHOR]
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- 2021
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24. Gammaherpesvirus Readthrough Transcription Generates a Long Non-Coding RNA That Is Regulated by Antisense miRNAs and Correlates with Enhanced Lytic Replication In Vivo.
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Kara, Mehmet, O'Grady, Tina, Feldman, Emily R., Feswick, April, Yiping Wang, Flemington, Erik K., and Tibbetts, Scott A.
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NON-coding RNA ,KAPOSI'S sarcoma-associated herpesvirus ,HAIRPIN (Genetics) ,ONCOGENIC viruses ,VIRAL genomes ,CHEMOKINES ,CD19 antigen - Abstract
Gammaherpesviruses, including the human pathogens Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are oncogenic viruses that establish lifelong infections in hosts and are associated with the development of lymphoproliferative diseases and lymphomas. Recent studies have shown that the majority of the mammalian genome is transcribed and gives rise to numerous long non-coding RNAs (lncRNAs). Likewise, the large double-stranded DNA virus genomes of herpesviruses undergo pervasive transcription, including the expression of many as yet uncharacterized lncRNAs. Murine gammaperherpesvirus 68 (MHV68, MuHV-4, HV68) is a natural pathogen of rodents, and is genetically and pathogenically related to EBV and KSHV, providing a highly tractable model for studies of gammaherpesvirus biology and pathogenesis. Through the integrated use of parallel data sets from multiple sequencing platforms, we previously resolved transcripts throughout the MHV68 genome, including at least 144 novel transcript isoforms. Here, we sought to molecularly validate novel transcripts identified within the M3/M2 locus, which harbors genes that code for the chemokine binding protein M3, the latency B cell signaling protein M2, and 10 microRNAs (miRNAs). Using strand-specific northern blots, we validated the presence of M3-04, a 3.91 kb polyadenylated transcript that initiates at the M3 transcription start site and reads through the M3 open reading frame (ORF), the M3 poly(a) signal sequence, and the M2 ORF. This unexpected transcript was solely localized to the nucleus, strongly suggesting that it is not translated and instead may function as a lncRNA. Use of an MHV68 mutant lacking two M3-04-antisense pre-miRNA stem loops resulted in highly increased expression of M3-04 and increased virus replication in the lungs of infected mice, demonstrating a key role for these RNAs in regulation of lytic infection. Together these findings suggest the possibility of a tripartite regulatory relationship between the lncRNA M3-04, antisense miRNAs, and the latency gene M2. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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25. Epigenetically Silenced Candidate Tumor Suppressor Genes in Prostate Cancer: Identified by Modeling Methylation Stratification and Applied to Progression Prediction.
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Wensheng Zhang, Flemington, Erik K., Hong-Wen Deng, and Kun Zhang
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Background: Recent studies have shown that epigenetic alterations, especially the hypermethylated promoters of tumor suppressor genes (TSGs), contribute to prostate cancer progression and metastasis. This article proposes a novel algorithm to identify epigenetically silenced TSGs (epi-TSGs) for prostate cancer. Methods: Our method is based on the perception that the promoter CpG island(s) of a typical epi-TSG has a stratified methylation profile over tumor samples. In other words, we assume that the methylation profile resembles the combination of a binary distribution of a driver mutation and a continuous distribution representing measurement noise and intratumor heterogeneity. Results: Applying the proposed algorithm and an existing method to The Cancer Genome Atlas prostate cancer data, we identify 57 candidate epi-TSGs. Over one third of these epi-TSGs have been reported to carry potential tumor suppression functions. The negative correlations between the expression levels and methylation levels of these genes are validated on external independent datasets. We further find that the expression profiling of these genes is a robust predictive signature for Gleason scores, with the AUC statistic ranging from 0.75 to 0.79. The identified signature also shows prediction strength for tumor progression stages, biochemical recurrences, and metastasis events. Conclusions: We propose a novel method for pinpointing candidate epi-TSGs in prostate cancer. The expression profiling of the identified epi-TSGs demonstrates significant prediction strength for tumor progression. Impact: The proposed epi-TSGs identification method can be adapted to other cancer types beyond prostate cancer. The identified clinically significant epi-TSGs would shed light on the carcinogenesis of prostate adenocarcinomas. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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26. The Epstein Barr virus circRNAome.
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Ungerleider, Nathan, Concha, Monica, Lin, Zhen, Roberts, Claire, Wang, Xia, Cao, Subing, Baddoo, Melody, Moss, Walter N., Yu, Yi, Seddon, Michael, Lehman, Terri, Tibbetts, Scott, Renne, Rolf, Dong, Yan, and Flemington, Erik K.
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DNA-binding proteins ,MOLECULAR biology ,HYDROLASES ,RNA sequencing ,HERPESVIRUSES - Abstract
Our appreciation for the extent of Epstein Barr virus (EBV) transcriptome complexity continues to grow through findings of EBV encoded microRNAs, new long non-coding RNAs as well as the more recent discovery of over a hundred new polyadenylated lytic transcripts. Here we report an additional layer to the EBV transcriptome through the identification of a repertoire of latent and lytic viral circular RNAs. Utilizing RNase R-sequencing with cell models representing latency types I, II, and III, we identified EBV encoded circular RNAs expressed from the latency Cp promoter involving backsplicing from the W1 and W2 exons to the C1 exon, from the EBNA BamHI U fragment exon, and from the latency long non-coding RPMS1 locus. In addition, we identified circular RNAs expressed during reactivation including backsplicing from exon 8 to exon 2 of the LMP2 gene and a highly expressed circular RNA derived from intra-exonic backsplicing within the BHLF1 gene. While expression of most of these circular RNAs was found to depend on the EBV transcriptional program utilized and the transcription levels of the associated loci, expression of LMP2 exon 8 to exon 2 circular RNA was found to be cell model specific. Altogether we identified over 30 unique EBV circRNAs candidates and we validated and determined the structural features, expression profiles and nuclear/cytoplasmic distributions of several predominant and notable viral circRNAs. Further, we show that two of the EBV circular RNAs derived from the RPMS1 locus are detected in EBV positive clinical stomach cancer specimens. This study increases the known EBV latency and lytic transcriptome repertoires to include viral circular RNAs and it provides an essential foundation and resource for investigations into the functions and roles of this new class of EBV transcripts in EBV biology and diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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27. Driver gene mutations based clustering of tumors: methods and applications.
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Zhang, Wensheng, Flemington, Erik K, and Zhang, Kun
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SOMATIC mutation , *PROTO-oncogenes , *CANCER genes , *COMPUTATIONAL biology , *COMPUTERS in biology , *MOLECULAR genetics - Abstract
Motivation: Somatic mutations in proto-oncogenes and tumor suppressor genes constitute a major category of causal genetic abnormalities in tumor cells. The mutation spectra of thousands of tumors have been generated by The Cancer Genome Atlas (TCGA) and other whole genome (exome) sequencing projects. A promising approach to utilizing these resources for precision medicine is to identify genetic similarity-based sub-types within a cancer type and relate the pinpointed sub-types to the clinical outcomes and pathologic characteristics of patients. Results: We propose two novel methods, ccpwModel and xGeneModel, for mutation-based clustering of tumors. In the former, binary variables indicating the status of cancer driver genes in tumors and the genes' involvement in the core cancer pathways are treated as the features in the clustering process. In the latter, the functional similarities of putative cancer driver genes and their confidence scores as the 'true' driver genes are integrated with the mutation spectra to calculate the genetic distances between tumors. We apply both methods to the TCGA data of 16 cancer types. Promising results are obtained when these methods are compared to state-of-the-art approaches as to the associations between the determined tumor clusters and patient race (or survival time). We further extend the analysis to detect mutation-characterized transcriptomic prognostic signatures, which are directly relevant to the etiology of carcinogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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28. Transferring knowledge of bacterial protein interaction networks to predict pathogen targeted human genes and immune signaling pathways: a case study on <italic>M. tuberculosis</italic>.
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Mei, Suyu, Flemington, Erik K., and Zhang, Kun
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IMMUNE response ,PROTEIN-protein interactions ,DRUG resistance ,MYCOBACTERIUM tuberculosis ,MICROBIAL virulence - Abstract
Background: Bacterial invasive infection and host immune response is fundamental to the understanding of pathogen pathogenesis and the discovery of effective therapeutic drugs. However, there are very few experimental studies on the signaling cross-talks between bacteria and human host to date. Methods: In this work, taking
M. tuberculosis H37Rv (MTB) that is co-evolving with its human host as an example, we propose a general computational framework that exploits the known bacterial pathogen protein interaction networks in STRING database to predict pathogen-host protein interactions and their signaling cross-talks. In this framework, significant interlogs are derived from the known pathogen protein interaction networks to train a predictive l2 -regularized logistic regression model. Results: The computational results show that the proposed method achieves excellent performance of cross validation as well as low predicted positive rates on the less significant interlogs and non-interlogs, indicating a low risk of false discovery. We further conduct gene ontology (GO) and pathway enrichment analyses of the predicted pathogen-host protein interaction networks, which potentially provides insights into the machinery thatM. tuberculosis H37Rv targets human genes and signaling pathways. In addition, we analyse the pathogen-host protein interactions related to drug resistance, inhibition of which potentially provides an alternative solution toM. tuberculosis H37Rv drug resistance. Conclusions: The proposed machine learning framework has been verified effective for predicting bacteria-host protein interactions via known bacterial protein interaction networks. For a vast majority of bacterial pathogens that lacks experimental studies of bacteria-host protein interactions, this framework is supposed to achieve a general-purpose applicability. The predicted protein interaction networks betweenM. tuberculosis H37Rv andHomo sapiens , provided in the Additional files, promise to gain applications in the two fields: (1) providing an alternative solution to drug resistance; (2) revealing the patterns thatM. tuberculosis H37Rv genes target human immune signaling pathways. [ABSTRACT FROM AUTHOR]- Published
- 2018
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29. Induction of a novel isoform of the lnc RNA HOTAIR in Claudin-low breast cancer cells attached to extracellular matrix.
- Author
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Li, Miao, Li, Xi, Zhuang, Yan, Flemington, Erik K., Lin, Zhen, and Shan, Bin
- Abstract
Elevated overexpression of the lnc RNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin-low MDA- MB-231 and Hs578T cells in two-dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin-rich extracellular matrix-based three-dimensional organotypic culture (lr ECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR-specific si RNA. Induction of HOTAIR in lr ECM 3D culture resulted from the activation of a novel isoform of HOTAIR ( HOTAIR-N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR-N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lr ECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR-N promoter in Claudin-low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin-low breast cancer cells in lr ECM 3D culture. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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30. A computational framework for distinguishing direct versus indirect interactions in human functional protein–protein interaction networks.
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Mei, Suyu, Flemington, Erik K., and Zhang, Kun
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- 2017
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31. Arsenic trioxide inhibits EBV reactivation and promotes cell death in EBV-positive lymphoma cells.
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Qinyan Yin, Sides, Mark, Parsons, Christopher H., Flemington, Erik K., and Lasky, Joseph A.
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ARSENIC trioxide ,EPSTEIN-Barr virus diseases ,HEMATOPOIESIS ,BURKITT'S lymphoma ,CANCER chemotherapy ,CELL death - Abstract
Background: Epstein-Barr Virus (EBV) is associated with hematopoietic malignancies, such as Burkitt's lymphoma, post-transplantation lymphoproliferative disorder, and diffuse large B-cell lymphoma. The current approach for EBVassociated lymphoma involves chemotherapy to eradicate cancer cells, however, normal cells may be injured and organ dysfunction may occur with currently employed regimens. This research is focused on employing arsenic trioxide (ATO) as EBV-specific cancer therapy takes advantage of the fact the EBV resides within the malignant cells. Methods and results: Our research reveals that low ATO inhibits EBV gene expression and genome replication. EBV spontaneous reactivation starts as early as 6 h after re-suspending EBV-positive Mutu cells in RPMI media in the absence of ATO, however this does not occur in Mutu cells cultured with ATO. ATO's inhibition of EBV spontaneous reactivation is dose dependent. The expression of the EBV immediate early gene Zta and early gene BMRF1 is blocked with low concentrations of ATO (0.5 nM - 2 nM) in EBV latency type I cells and EBV-infected PBMC cells. The combination of ATO and ganciclovir further diminishes EBV gene expression. ATO-mediated reduction of EBV gene expression can be rescued by co-treatment with the proteasome inhibitor MG132, indicating that ATO promotes ubiquitin conjugation and proteasomal degradation of EBV genes. Co-immunoprecipitation assays with antibodies against Zta pulls down more ubiquitin in ATO treated cell lysates. Furthermore, MG132 reverses the inhibitory effect of ATO on anti-IgM-, PMA- and TGF-β-mediated EBV reactivation. Thus, mechanistically ATO's inhibition of EBV gene expression occurs via the ubiquitin pathway. Moreover, ATO treatment results in increased cell death in EBV-positive cells compared to EBV-negative cells, as demonstrated by both MTT and trypan blue assays. ATO-induced cell death in EBV-positive cells is dose dependent. ATO and ganciclovir in combination further enhances cell death specifically in EBV-positive cells. Conclusion: ATO-mediated inhibition of EBV lytic gene expression results in cell death selectively in EBV-positive lymphocytes, suggesting that ATO may potentially serve as a drug to treat EBV-related lymphomas in the clinical setting. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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32. A comprehensive approach to expression of L1 loci.
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Deininger, Prescott, Morales, Maria E., White, Travis B., Baddoo, Melody, Hedges, Dale J., Servant, Geraldine, Srivastav, Sudesh, Smither, Madison E., Concha, Monica, DeHaro, Dawn L., Flemington, Erik K., and Belancio, Victoria P.
- Published
- 2017
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33. SpliceTools, a suite of downstream RNA splicing analysis tools to investigate mechanisms and impact of alternative splicing.
- Author
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Flemington, Erik K, Flemington, Samuel A, O'Grady, Tina M, Baddoo, Melody, Nguyen, Trang, Dong, Yan, and Ungerleider, Nathan A
- Published
- 2023
- Full Text
- View/download PDF
34. Global transcript structure resolution of high gene density genomes through multi-platform data integration.
- Author
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O'Grady, Tina, Xia Wang, Höner zu Bentrup, Kerstin, Baddoo, Melody, Concha, Monica, and Flemington, Erik K.
- Published
- 2016
- Full Text
- View/download PDF
35. Mutant TP53 disrupts age-related accumulation patterns of somatic mutations in multiple cancer types.
- Author
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Zhang, Wensheng, Flemington, Erik K., and Zhang, Kun
- Subjects
- *
P53 protein , *SOMATIC mutation , *PROTO-oncogenes , *TUMOR suppressor genes ,TUMOR genetics ,AGE factors in cancer - Abstract
Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes. Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm. The risk of sporadic mutations increases with age. In this regard, a positive association between patient age and the accumulated mutation burden in tumors exists for many cancer types. However, the reported lines of evidence for such a connection are still limited. TP53 is the most frequently mutated cancer gene. The encoded p53 protein plays crucial roles in DNA repair. Hereby, we speculate that mutant TP53 can disrupt the age-related accumulation patterns of somatic mutations in tumors. We performed linear model analysis on the clinically-annotated genomic data published by TCGA. We found that there was a significant interaction between TP53 genotype (mutant versus wild-type) and patient age at the initial clinical date on somatic mutation burden for five cancers. That is, the regression coefficients of mutation burden on patient age were significant (p < 0.05) for TP53 wild-type tumors but not the mutant counterparts. This disparity was further verified by comparing the group-specific regression coefficients. This finding confirmed our hypothesis and provided unique insights into p53-related tumorigenesis such as the potential temporal order of driver mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
36. A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus - tumor association.
- Author
-
Strong, Michael J., Blanchard 4th, Eugene, Zhen Lin, Morris, Cindy A., Baddoo, Melody, Taylor, Christopher M., Ware, Marcus L., and Flemington, Erik K.
- Subjects
CYTOMEGALOVIRUSES ,BRAIN tumors ,GLIOMAS - Abstract
Next generation sequencing (NGS) can globally interrogate the genetic composition of biological samples in an unbiased yet sensitive manner. The objective of this study was to utilize the capabilities of NGS to investigate the reported association between glioblastoma multiforme (GBM) and human cytomegalovirus (HCMV). A large-scale comprehensive virome assessment was performed on publicly available sequencing datasets from the Cancer Genome Atlas (TCGA), including RNA-seq datasets from primary GBM (n = 157), recurrent GBM (n = 13), low-grade gliomas (n = 514), recurrent low-grade gliomas (n = 17), and normal brain (n = 5), and whole genome sequencing (WGS) datasets from primary GBM (n = 51), recurrent GBM (n = 10), and normal matched blood samples (n = 20). In addition, RNA-seq datasets from MRI-guided biopsies (n = 92) and glioma stem-like cell cultures (n = 9) were analyzed. Sixty-four DNA-seq datasets from 11 meningiomas and their corresponding blood control samples were also analyzed. Finally, three primary GBM tissue samples were obtained, sequenced using RNA-seq, and analyzed. After in-depth analysis, the most robust virus findings were the detection of papillomavirus (HPV) and hepatitis B reads in the occasional LGG sample (4 samples and 1 sample, respectively). In addition, low numbers of virus reads were detected in several datasets but detailed investigation of these reads suggest that these findings likely represent artifacts or non-pathological infections. For example, all of the sporadic low level HCMV reads were found to map to the immediate early promoter intimating that they likely originated from laboratory expression vector contamination. Despite the detection of low numbers of Epstein-Barr virus reads in some samples, these likely originated from infiltrating B-cells. Finally, human herpesvirus 6 and 7 aligned viral reads were identified in all DNA-seq and a few RNA-seq datasets but detailed analysis demonstrated that these were likely derived from the homologous human telomeric-like repeats. Other low abundance viral reads were detected in some samples but for most viruses, the reads likely represent artifacts or incidental infections. This analysis argues against associations between most known viruses and GBM or mengiomas. Nevertheless, there may be a low percentage association between HPV and/or hepatitis B and LGGs. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
37. Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator.
- Author
-
Xiang Zhou, Qian Hao, Peng Liao, Shiwen Luo, Minhong Zhang, Guohui Hu, Hongbing Liu, Yiwei Zhang, Bo Cao, Baddoo, Melody, Flemington, Erik K., Zeng, Shelya X., and Hua Lu
- Published
- 2016
- Full Text
- View/download PDF
38. Microbial Contamination in Next Generation Sequencing: Implications for Sequence-Based Analysis of Clinical Samples.
- Author
-
Strong, Michael J., Xu, Guorong, Morici, Lisa, Splinter Bon-Durant, Sandra, Baddoo, Melody, Lin, Zhen, Fewell, Claire, Taylor, Christopher M., and Flemington, Erik K.
- Subjects
MICROBIAL contamination ,PATHOGENIC microorganisms ,RNA sequencing ,NUCLEOTIDE sequence ,NUCLEOTIDE sequencing - Abstract
The high level of accuracy and sensitivity of next generation sequencing for quantifying genetic material across organismal boundaries gives it tremendous potential for pathogen discovery and diagnosis in human disease. Despite this promise, substantial bacterial contamination is routinely found in existing human-derived RNA-seq datasets that likely arises from environmental sources. This raises the need for stringent sequencing and analysis protocols for studies investigating sequence-based microbial signatures in clinical samples. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
39. Circulating Exosomal Proteins are linked to Neuropathogenesis in SIV‐infected Rhesus Macaque: A Proteomic Approach.
- Author
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Chandra, Partha K., Braun, Stephen E., Baddoo, Melody C., Kim, Hogyoung, Castorena‐Gonzalez, Jorge A., Cikic, Sinisa, Rutkai, Ibolya, Guidry, Jessie J., Worthylake, David K., Flemington, Erik K., Abdel‐Mageed, Asim B., and Busija, David W.
- Published
- 2022
- Full Text
- View/download PDF
40. microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity.
- Author
-
Martin, Elizabeth C., Rhodes, Lyndsay V., Elliott, Steven, Krebs, Adrienne E., Nephew, Kenneth P., Flemington, Erik K., Collins-Burow, Bridgette M., and Burow, Matthew E.
- Subjects
RAPAMYCIN ,ESTROGEN receptors ,CELL proliferation ,GENE expression ,BREAST cancer ,MICRORNA - Abstract
Background: The AKT/mammalian target of rapamycin (mTOR) signaling pathway is regulated by 17α-estradiol (E2) signaling and mediates E2-induced proliferation and progesterone receptor (PgR) expression in breast cancer. Methods and results: Here we use deep sequencing analysis of previously published data from The Cancer Genome Atlas to demonstrate that expression of a key component of mTOR signaling, rapamycin-insensitive companion of mTOR (Rictor), positively correlated with an estrogen receptor-α positive (ERα
+ ) breast tumor signature. Through increased microRNA-155 (miR-155) expression in the ERα+ breast cancer cells we demonstrate repression of Rictor enhanced activation of mTOR complex 1 (mTORC1) signaling with both qPCR and western blot. miR-155-mediated mTOR signaling resulted in deregulated ERα signaling both in cultured cells in vitro and in xenografts in vivo in addition to repressed PgR expression and activity. Furthermore we observed that miR-155 enhanced mTORC1 signaling (observed through western blot for increased phosphorylation on mTOR S2448) and induced inhibition of mTORC2 signaling (evident through repressed Rictor and tuberous sclerosis 1 (TSC1) gene expression). mTORC1 induced deregulation of E2 signaling was confirmed using qPCR and the mTORC1-specific inhibitor RAD001. Co-treatment of MCF7 breast cancer cells stably overexpressing miR-155 with RAD001 and E2 restored E2-induced PgR gene expression. RAD001 treatment of SCID/CB17 mice inhibited E2-induced tumorigenesis of the MCF7 miR-155 overexpressing cell line. Finally we demonstrated a strong positive correlation between Rictor and PgR expression and a negative correlation with Raptor expression in Luminal B breast cancer samples, a breast cancer histological subtype known for having an altered ERα-signaling pathway. Conclusions: miRNA mediated alterations in mTOR and ERα signaling establishes a new mechanism for altered estrogen responses independent of growth factor stimulation. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
41. Ebola virus delta peptide is an enterotoxin.
- Author
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Melnik, Lilia I., Guha, Shantanu, Ghimire, Jenisha, Smither, Allison R., Beddingfield, Brandon J., Hoffmann, Andrew R., Sun, Leisheng, Ungerleider, Nathan A., Baddoo, Melody C., Flemington, Erik K., Gallaher, William R., Wimley, William C., and Garry, Robert F.
- Abstract
During the 2013–2016 West African (WA) Ebola virus (EBOV) outbreak, severe gastrointestinal symptoms were common in patients and associated with poor outcome. Delta peptide is a conserved product of post-translational processing of the abundant EBOV soluble glycoprotein (sGP). The murine ligated ileal loop model was used to demonstrate that delta peptide is a potent enterotoxin. Dramatic intestinal fluid accumulation follows injection of biologically relevant amounts of delta peptide into ileal loops, along with gross alteration of villous architecture and loss of goblet cells. Transcriptomic analyses show that delta peptide triggers damage response and cell survival pathways and downregulates expression of transporters and exchangers. Induction of diarrhea by delta peptide occurs via cellular damage and regulation of genes that encode proteins involved in fluid secretion. While distinct differences exist between the ileal loop murine model and EBOV infection in humans, these results suggest that delta peptide may contribute to EBOV-induced gastrointestinal pathology. [Display omitted] • Delta peptide is a potent enterotoxin • Injection of delta peptide into murine ileal loops induces fluid accumulation • Delta peptide downregulates the expression of ion transporters and other exchangers • Delta peptide may present a potential therapeutic target Melnik et al. use the murine ligated ileal loop model to demonstrate that delta peptide is a potent enterotoxin. Intestinal fluid accumulation, alteration of villous architecture, and loss of goblet cells follow injection of delta peptide. Delta peptide induces diarrhea via direct cellular damage and regulation of fluid secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
42. Genome-wide Transcript Structure Resolution Reveals Abundant Alternate Isoform Usage from Murine Gammaherpesvirus 68.
- Author
-
O'Grady, Tina, Feswick, April, Hoffman, Brett A., Wang, Yiping, Medina, Eva M., Kara, Mehmet, van Dyk, Linda F., Flemington, Erik K., and Tibbetts, Scott A.
- Abstract
The gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68), are etiologic agents of a wide range of lymphomas and non-hematological malignancies. These viruses possess large and highly dense dsDNA genomes that feature >80 bidirectionally positioned open reading frames (ORFs). The abundance of overlapping transcripts and extensive splicing throughout these genomes have until now prohibited high throughput-based resolution of transcript structures. Here, we integrate the capabilities of long-read sequencing with the accuracy of short-read platforms to globally resolve MHV68 transcript structures using the transcript resolution through integration of multi-platform data (TRIMD) pipeline. This approach reveals highly complex features, including: (1) pervasive overlapping transcript structures; (2) transcripts containing intra-gene or trans-gene splices that yield chimeric ORFs; (3) antisense and intergenic transcripts containing ORFs; and (4) noncoding transcripts. This work sheds light on the underappreciated complexity of gammaherpesvirus transcription and provides an extensively revised annotation of the MHV68 transcriptome. • Global resolution of transcript isoforms during lytic gammaherpesvirus infection • Genome-wide alternate isoform usage and readthrough transcription • Resolution of 258 transcript structures, including overlapping isoforms • Identification of long noncoding RNAs and unexpected ORFs The highly dense dsDNA genomes of herpesviruses feature an abundance of overlapping transcripts and extensive splicing, greatly hindering the global identification of individual transcripts. O'Grady et al. use integrated multi-platform genomics to globally resolve transcript structures from murine gammaherpesvirus 68, providing an extensively revised genome annotation. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
43. Detection of Epstein-Barr Virus Infection in Non-Small Cell Lung Cancer.
- Author
-
Kheir, Fayez, Zhao, Mengmeng, Strong, Michael J., Yu, Yi, Nanbo, Asuka, Flemington, Erik K., Morris, Gilbert F., Reiss, Krzysztof, Li, Li, and Lin, Zhen
- Subjects
ADENOCARCINOMA ,CELLULAR signal transduction ,EPSTEIN-Barr virus diseases ,GENE expression ,LUNG cancer ,RNA ,SQUAMOUS cell carcinoma ,GENE expression profiling ,SEQUENCE analysis ,IN vivo studies - Abstract
Previous investigations proposed a link between the Epstein-Barr virus (EBV) and lung cancer (LC), but the results are highly controversial largely due to the insufficient sample size and the inherent limitation of the traditional viral screening methods such as PCR. Unlike PCR, current next-generation sequencing (NGS) utilizes an unbiased method for the global assessment of all exogenous agents within a cancer sample with high sensitivity and specificity. In our current study, we aim to resolve this long-standing controversy by utilizing our unbiased NGS-based informatics approaches in conjunction with traditional molecular methods to investigate the role of EBV in a total of 1127 LC. In situ hybridization analysis of 110 LC and 10 normal lung samples detected EBV transcripts in 3 LC samples. Comprehensive virome analyses of RNA sequencing (RNA-seq) data sets from 1017 LC and 110 paired adjacent normal lung specimens revealed EBV transcripts in three lung squamous cell carcinoma and one lung adenocarcinoma samples. In the sample with the highest EBV coverage, transcripts from the BamHI A region accounted for the majority of EBV reads. Expression of EBNA-1, LMP-1 and LMP-2 was observed. A number of viral circular RNA candidates were also detected. Thus, we for the first time revealed a type II latency-like viral transcriptome in the setting of LC in vivo. The high-level expression of viral BamHI A transcripts in LC suggests a functional role of these transcripts, likely as long non-coding RNA. Analyses of cellular gene expression and stained tissue sections indicated an increased immune cell infiltration in the sample expressing high levels of EBV transcripts compared to samples expressing low EBV transcripts. Increased level of immune checkpoint blockade factors was also detected in the sample with higher levels of EBV transcripts, indicating an induced immune tolerance. Lastly, inhibition of immune pathways and activation of oncogenic pathways were detected in the sample with high EBV transcripts compared to the EBV-low LC indicating the direct regulation of cancer pathways by EBV. Taken together, our data support the notion that EBV likely plays a pathological role in a subset of LC. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
44. Interleukin-17A in the Pathogenesis of Lung Adenocarcinoma.
- Author
-
Zhen Lin, Nguyen, Christian, Beibei Xu, Flemington, Erik K., and Morris, Gilbert F.
- Published
- 2018
- Full Text
- View/download PDF
45. Screen technical noise in single cell RNA sequencing data.
- Author
-
Bai, Yu-Long, Baddoo, Melody, Flemington, Erik K., Nakhoul, Hani N., and Liu, Yao-Zhong
- Subjects
- *
RNA sequencing , *GENE libraries , *DATA scrubbing , *GENE expression , *NOISE - Abstract
We proposed a data cleaning pipeline for single cell (SC) RNA-seq data, where we first screen genes (gene-wise screening) followed by screening cell libraries (library-wise screening). Gene-wise screening is based on the expectation that for a gene with a low technical noise, a gene's count in a library will tend to increase with the increase of library size, which was tested using negative binomial regression of gene count (as dependent variable) against library size (as independent variable). Library-wise screening is based on the expectation that across-library correlations for housekeeping (HK) genes is expected to be higher than the correlations for non-housekeeping (NHK) genes in those libraries with low technical noise. We removed those libraries, whose mean pairwise correlation for HK genes is NOT significantly higher than that for NHK genes. We successfully applied the pipeline to two large SC RNA-seq datasets. The pipeline was also developed into an R package. • Single cell RNA sequencing measures gene expression at level of individual cells. • Single cell RNA sequencing data normally contain a lot of technical noise. • A pipeline is proposed to clean the technical noise based on housekeeping genes. • The pipeline is based on rigorous statistical analyses that avoid arbitrary cut off. • A software program is available to implement the pipeline. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
46. Integrative Genomics and Transcriptomics Analysis Reveals Potential Mechanisms for Favorable Prognosis of Patients with HPV-Positive Head and Neck Carcinomas.
- Author
-
Zhang, Wensheng, Edwards, Andrea, Fang, Zhide, Flemington, Erik K., and Zhang, Kun
- Published
- 2016
- Full Text
- View/download PDF
47. Increased transcription and high translation efficiency lead to accumulation of androgen receptor splice variant after androgen deprivation therapy.
- Author
-
Ma, Tianfang, Bai, Shanshan, Qi, Yanfeng, Zhan, Yang, Ungerleider, Nathan, Zhang, Derek Y., Neklesa, Taavi, Corey, Eva, Dehm, Scott M., Zhang, Kun, Flemington, Erik K., and Dong, Yan
- Subjects
- *
ANDROGEN deprivation therapy , *ANDROGEN receptors , *CASTRATION-resistant prostate cancer , *HORMONE therapy - Abstract
Upregulation of androgen receptor splice variants (AR-Vs), especially AR-V7, is associated with castration resistance of prostate cancer. At the RNA level, AR-V7 upregulation is generally coupled with increased full-length AR (AR-FL); consequently, AR-V7 and AR-Vs collectively constitute a minority of the AR population. However, Western blotting showed that the relative abundance of AR-V proteins is much higher in many castration-resistant prostate cancers (CRPCs). To address the mechanism underlying this discrepancy, we analyzed RNA-seq data from ~350 CRPC samples and found a positive correlation between all canonical and alternative AR splicing. This indicates that increased alternative splicing is not at the expense of canonical splicing. Instead, androgen deprivation releases AR-FL from repressing the transcription of the AR gene to induce coordinated increase of AR-FL and AR-V mRNAs. At the protein level, however, androgen deprivation induces AR-FL, but not AR-V, degradation. Moreover, AR-V7 is translated much faster than AR-FL. Thus, androgen-deprivation-induced AR-gene transcription and AR-FL protein decay, together with efficient AR-V7 translation, explain the discrepancy between the relative AR-V mRNA and protein abundances in many CRPCs, highlighting the inevitability of AR-V induction after endocrine therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
48. Comparative Analysis of Gammaherpesvirus Circular RNA Repertoires: Conserved and Unique Viral Circular RNAs.
- Author
-
Ungerleider, Nathan A., Jain, Vaibhav, Yiping Wang, Maness, Nicholas J., Blair, Robert V., Alvarez, Xavier, Midkiff, Cecily, Kolson, Dennis, Bai, Shanshan, Roberts, Claire, Moss, Walter N., Xia Wang, Serfecz, Jacqueline, Seddon, Michael, Lehman, Terri, Tianfang Ma, Yan Dong, Renne, Rolf, Tibbetts, Scott A., and Flemington, Erik K.
- Subjects
- *
CIRCULAR RNA , *KAPOSI'S sarcoma - Abstract
Recent studies have identified circular RNAs (circRNAs) expressed from the Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) human DNA tumor viruses. To gain initial insights into the potential relevance of EBV circRNAs in virus biology and disease, we assessed the circRNAome of the interspecies homologue rhesus macaque lymphocryptovirus (rLCV) in a naturally occurring lymphoma from a simian immunodeficiency virus (SIV)-infected rhesus macaque. This analysis revealed rLCV orthologues of the latency-associated EBV circular RNAs circRPMS1_E4_E3a and circEBNA_U. Also identified in two samples displaying unusually high lytic gene expression was a novel rLCV circRNA that contains both conserved and rLCV-specific RPMS1 exons and whose backsplice junctions flank an rLCV lytic origin of replication (OriLyt). Analysis of a lytic infection model for the murid herpesvirus 68 (MHV68) rhadinovirus identified a cluster of circRNAs near an MHV68 lytic origin of replication, with the most abundant of these, circM11_ORF69, spanning the OriLyt. Lastly, analysis of KSHV latency and reactivation models revealed the latency associated circRNA originating from the vIRF4 gene as the predominant viral circRNA. Together, the results of this study broaden our appreciation for circRNA repertoires in the Lymphocryptovirus and Rhadinovirus genera of gammaherpesviruses and provide evolutionary support for viral circRNA functions in latency and viral replication. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
49. Maintenance of AP-2-Dependent Functional Activities of Nef Restricts Pathways of Immune Escape from CD8 T Lymphocyte Responses.
- Author
-
Schouest, Blake, Weiler, Andrea M., Janaka, Sanath Kumar, Myers, Tereance A., Das, Arpita, Wilder, Sarah C., Furlott, Jessica, Baddoo, Melody, Flemington, Erik K., Rakasz, Eva G., Evans, David T., Friedrich, Thomas C., and Maness, Nicholas J.
- Subjects
- *
LENTIVIRUSES , *T cells , *ACTIVATOR protein-2 transcription factors , *EPITOPES , *IMMUNOREGULATION , *IMMUNE response - Abstract
Nef-specific CD8+ T lymphocytes (CD8TL) are linked to extraordinary control of primate lentiviral replication, but the mechanisms underlying their efficacy remain largely unknown. The immunodominant, Mamu-B*017:01+-restricted Nef195-203MW9 epitope in SIVmac239 partially overlaps a sorting motif important for interactions with host AP-2 proteins and, hence, downmodulation of several host proteins, including Tetherin (CD317/BST-2), CD28, CD4, SERINC3, and SERINC5. We reasoned that CD8TL-driven evolution in this epitope might compromise Nef's ability to modulate these important molecules. Here, we used deep sequencing of SIV from nine B*017:01+ macaques throughout infection with SIVmac239 to characterize the patterns of viral escape in this epitope and then assayed the impacts of these variants on Nef-mediated modulation of multiple host molecules. Acute variation in multiple Nef195-203MW9 residues significantly compromised Nef's ability to downregulate surface Tetherin, CD4, and CD28 and reduced its ability to prevent SERINC5-mediated reduction in viral infectivity but did not impact downregulation of CD3 or major histocompatibility complex class I, suggesting the selective disruption of immunomodulatory pathways involving Nef AP-2 interactions. Together, our data illuminate a pattern of viral escape dictated by a selective balance to maintain AP-2-mediated downregulation while evading epitope-specific CD8TL responses. These data could shed light on mechanisms of both CD8TL-driven viral control generally and on Mamu-B*017:01-mediated viral control specifically. IMPORTANCE A rare subset of humans infected with HIV-1 and macaques infected with SIV can control the virus without aid of antiviral medications. A common feature of these individuals is the ability to mount unusually effective CD8 T lymphocyte responses against the virus. One of the most formidable aspects of HIV is its ability to evolve to evade immune responses, particularly CD8 T lymphocytes. We show that macaques that target a specific peptide in the SIV Nef protein are capable of better control of the virus and that, as the virus evolves to escape this response, it does so at a cost to specific functions performed by the Nef protein. Our results help show how the virus can be controlled by an immune response, which could help in designing effective vaccines. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
50. Methylation status and AP1 elements are involved in EBV-mediated miR-155 expression in EBV positive lymphoma cells.
- Author
-
Yin, Qinyan, Wang, Xia, Roberts, Claire, Flemington, Erik K., and Lasky, Joseph A.
- Subjects
- *
MICRORNA , *GENE expression , *EPSTEIN-Barr virus , *DNA methylation , *TRANSCRIPTION factors , *CELL communication - Abstract
The relationship between Epstein Barr Virus (EBV) and miR-155 is well established. EBV infection induces miR-155 expression, which is expressed at higher levels in EBV latency type III cells compared to EBV latency type I cells. However, the mechanism by which EBV latency genes activate miR-155 expression is still unclear. Here we present data showing that DNA methylation regulates miR-155 expression. We also provide evidence that the AP1 signaling pathway is involved in EBV-mediated miR-155 activation, and that Bay11 influences signaling of the miR-155 promoter AP1 element. Lastly, we show that LMP2A, LMP1 and EBNAs cannot activate miR-155 expression alone, indicating that the regulation of miR-155 by EBV is dependent on more than one EBV gene or cell signaling pathway. We conclude that the regulation of miR-155 in EBV-positive cells occurs through multiple cell signaling processes involving EBV-mediated chromatin remodeling, cell signaling regulation and transcription factor activation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
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