18 results on '"Abraham S. Weintraub"'
Search Results
2. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism
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Richard A. Young, John C. Manteiga, Jurian Schuijers, Tong Ihn Lee, Daniel S. Day, Alicia V. Zamudio, Denes Hnisz, Abraham S. Weintraub, Massachusetts Institute of Technology. Department of Biology, Manteiga, John Colonnese, Weintraub, Abraham Selby, Zamudio Montes de Oca, Alicia, and Young, Richard A
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0301 basic medicine ,CCCTC-Binding Factor ,Cell type ,Amino Acid Motifs ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Cell Line, Tumor ,Gene expression ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Enhancer ,lcsh:QH301-705.5 ,Gene ,Cell Proliferation ,Gene Editing ,Regulation of gene expression ,Binding Sites ,Oncogene ,DNA Methylation ,Cell biology ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,030104 developmental biology ,lcsh:Biology (General) ,DNA methylation ,CRISPR-Cas Systems ,Protein Binding - Abstract
Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types., National Institutes of Health (U.S.) (grant HG002668), Virginia and Daniel K. Ludwig Graduate Fellowship, National Science Foundation (U.S.). Graduate Research Fellowship Program
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- 2018
3. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma
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Shan Lin, Amy Saur Conway, Biniam Adane, Amanda Balboni Iniguez, Richard A. Young, Neekesh V. Dharia, Elizabeth Hwang, Francisca Vazquez, Filemon S. Dela Cruz, Diana Lu, Kimberly Stegmaier, Gabriela Alexe, John M. Krill-Burger, Caleb A. Lareau, Bo Kyung A. Seong, Jason N. Berman, Andrew L. Kung, Benjamin Tanenbaum, Monica Schenone, Martin J. Aryee, Denes Hnisz, Amanda L. Robichaud, Melissa Richardson, Linda Ross, Brian D. Crompton, Abraham S. Weintraub, Steven A. Carr, and Sarah Wang
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0301 basic medicine ,Cancer Research ,Oncogene Proteins, Fusion ,Chromosomal Proteins, Non-Histone ,Bone Neoplasms ,Cell Cycle Proteins ,Sarcoma, Ewing ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Mice, Inbred NOD ,Cell Line, Tumor ,Animals ,Humans ,Promoter Regions, Genetic ,Enhancer ,Transcription factor ,Zebrafish ,Homeodomain Proteins ,Regulation of gene expression ,biology ,Cohesin ,Proto-Oncogene Protein c-fli-1 ,Polycomb Repressive Complex 2 ,Nuclear Proteins ,Xenograft Model Antitumor Assays ,Chromatin ,Cell biology ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,FLI1 ,POU Domain Factors ,biology.protein ,Female ,RNA-Binding Protein EWS ,PRC2 ,Reprogramming - Abstract
The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Herein, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2) marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells, the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.
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- 2021
4. PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes
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Richard A. Young, Michael T. Hemann, Francisco J. Sánchez-Rivera, Jordan M. E. Bartlebaugh, Tyler Jacks, Christine S. Cheng, Aviv Regev, Arjun Bhutkar, Abraham S. Weintraub, Yunpeng Liu, Jason D. Buenrostro, and Yadira M. Soto-Feliciano
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0301 basic medicine ,Lineage (genetic) ,Biology ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Leukemia, B-Cell ,Genetics ,Animals ,Nucleosome ,Cell Lineage ,Gene ,Transcription factor ,ChIA-PET ,Homeodomain Proteins ,Lymphoma, Non-Hodgkin ,Chromatin ,3. Good health ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Repressor Proteins ,Phenotype ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Homeobox ,Developmental biology ,Research Paper ,Signal Transduction ,Developmental Biology - Abstract
Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell- and T-cell-specific factors. Additionally, Phf6KO cells show significant down-regulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.
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- 2017
5. APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL
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Theresa E. Leon, Jinghui Zhang, Adele K. Fielding, Nadine Farah, Zhaodong Li, Yu Liu, Alla Berezovskaya, Takaomi Sanda, Shuhong Shen, Marc R. Mansour, Brian J. Abraham, Richard A. Young, Shi Hao Tan, Benshang Li, Abraham S. Weintraub, A T Look, Massachusetts Institute of Technology. Department of Biology, and Young, Richard A
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0301 basic medicine ,APOBEC ,Chromatin Immunoprecipitation ,Cancer Research ,Genes, myb ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Jurkat Cells ,Proto-Oncogene Proteins c-myb ,03 medical and health sciences ,Germline mutation ,Cell Line, Tumor ,medicine ,Humans ,Point Mutation ,APOBEC Deaminases ,RNA, Small Interfering ,Child ,Enhancer ,Gene ,Genetics ,Mutation ,Binding Sites ,Base Sequence ,Transition (genetics) ,Gene Expression Regulation, Leukemic ,Point mutation ,DNA, Neoplasm ,Hematology ,Cytidine deaminase ,LIM Domain Proteins ,Neoplasm Proteins ,3. Good health ,DNA-Binding Proteins ,Enhancer Elements, Genetic ,030104 developmental biology ,Oncology ,RNA Interference ,Original Article ,5' Untranslated Regions ,Transcriptome ,Transcription Factors - Abstract
Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well., National Institutes of Health (U.S.) (Grant 5P01CA109901)
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- 2017
6. Activation of proto-oncogenes by disruption of chromosome neighborhoods
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Alla A. Sigova, Matthew H. Porteus, Anne-Laure Valton, Bryan R. Lajoie, Rasmus O. Bak, Abraham S. Weintraub, Job Dekker, Daniel S. Day, Johanna Goldmann, Tong Ihn Lee, Rudolf Jaenisch, Charles H. Li, Denes Hnisz, Richard A. Young, Jessica Reddy, Diego Borges-Rivera, and Zi Peng Fan
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Transcriptional Activation ,0301 basic medicine ,Proto-Oncogenes ,T cell ,Chromosomal translocation ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Genome ,Translocation, Genetic ,Fusion gene ,03 medical and health sciences ,medicine ,Humans ,Sequence Deletion ,Chromosome Aberrations ,Genetics ,Regulation of gene expression ,Multidisciplinary ,Gene Expression Regulation, Leukemic ,HEK 293 cells ,Chromosome Mapping ,Cell biology ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,Cancer cell - Abstract
The spread of bad neighborhoods Our genomes have complex three-dimensional (3D) arrangements that partition and regulate gene expression. Cancer cells frequently have their genomes grossly rearranged, disturbing this intricate 3D organization. Hnisz et al. show that the disruption of these 3D neighborhoods can bring oncogenes under the control of regulatory elements normally kept separate from them (see the Perspective by Wala and Beroukim). These novel juxtapositions can result in the inappropriate activation of oncogenes. Science , this issue p. 1454 ; see also p. 1398
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- 2016
7. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas
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Geneive Carrión-Grant, Roland Goldbrunner, Brian J. Abraham, Akdes Serin Harmanci, Octavian Henegariu, Daniel Duran, Johanna Goldmann, Tong Ihn Lee, Matthias Simon, Katsuhito Yasuno, Hanwen Bai, Alexander O. Vortmeyer, Jacob F Baranoski, Ketu Mishra-Gorur, Joseph M. Piepmeier, Victoria E. Clark, Kaya Bilguvar, Abraham S. Weintraub, A. Gulhan Ercan-Sencicek, Boris Krischek, Mark W. Youngblood, Richard A. Young, Murat Gunel, Denes Hnisz, E. Zeynep Erson-Omay, Johannes Schramm, and Jennifer Moliterno Günel
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0301 basic medicine ,Genotype ,Somatic cell ,Chromosomes, Human, Pair 22 ,DNA Mutational Analysis ,Kruppel-Like Transcription Factors ,RNA polymerase II ,medicine.disease_cause ,Article ,Cohort Studies ,03 medical and health sciences ,Kruppel-Like Factor 4 ,Transcription (biology) ,Catalytic Domain ,Genetics ,medicine ,Meningeal Neoplasms ,Humans ,Exome ,POLR2A ,Gene ,Neurofibromin 2 ,biology ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Enhancer Elements, Genetic ,KLF4 ,Mutation ,biology.protein ,RNA Polymerase II ,Carcinogenesis ,Meningioma - Abstract
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes2, 3, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO4, 5, 6, 7, 8, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
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- 2016
8. Small genomic insertions form enhancers that misregulate oncogenes
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Abraham S. Weintraub, Zhaodong Li, Brian J. Abraham, Julia Etchin, Marc R. Mansour, Richard A. Young, A. Thomas Look, Shuhong Shen, Tong Ihn Lee, Benshang Li, Sunniyat Rahman, Nicholas Kwiatkowski, Jinghui Zhang, Yu Liu, Nina Weichert-Leahey, Charles H. Li, Denes Hnisz, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Abraham, Brian Joseph, Weintraub, Abraham Selby, Kwiatkowski, Nick, Li, Charles Han, Lee, Tong Ihn, and Young, Richard A
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0301 basic medicine ,Adult ,Adolescent ,Somatic cell ,Science ,General Physics and Astronomy ,Biology ,medicine.disease_cause ,Genome ,Article ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Enhancer ,Child ,Genetics ,Multidisciplinary ,Base Sequence ,Gene Expression Regulation, Leukemic ,Genome, Human ,Mutagenesis ,Infant ,Reproducibility of Results ,General Chemistry ,Oncogenes ,Corrigenda ,3. Good health ,Mutagenesis, Insertional ,030104 developmental biology ,Enhancer Elements, Genetic ,chemistry ,Child, Preschool ,Human genome ,Carcinogenesis ,DNA - Abstract
The non-coding regions of tumour cell genomes harbour a considerable fraction of total DNA sequence variation, but the functional contribution of these variants to tumorigenesis is ill-defined. Among these non-coding variants, somatic insertions are among the least well characterized due to challenges with interpreting short-read DNA sequences. Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants. Among the 102 tumour cell genomes we analyse, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukaemia tumour genomes, reveals that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The approach described here to identify enhancer-associated small insertion variants provides a foundation for further study of these abnormalities across human cancers., United States. National Institutes of Health (HG002668), United States. National Institutes of Health (CA109901)
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- 2016
9. Abstract 971: Three-dimensional gene regulatory landscapes in normal and cancer cells
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Abraham S. Weintraub, Tong Ihn Lee, Yang Eric Guo, Brian J. Abraham, Charles H. Li, Denes Hnisz, Richard A. Young, Jurian Schuijers, and Daniel S. Day
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Cancer Research ,Oncology ,Cancer cell ,Cancer research ,Biology ,Gene - Abstract
Key oncogenes can be misregulated in tumor cells by the acquisition of tumor-specific enhancers that direct gene expression through physical contacts (1,2). Identifying the full complement of enhancers regulating each oncogene could identify additional vulnerabilities in tumor expression programs, but remains challenging, because a given enhancer can regulate multiple genes and each of its targets may be genomically distant. Here we use DNA interaction data to construct gene regulatory landscapes for all expressed genes in a tumor cell and demonstrate that sets of enhancers can be assigned to these oncogenes using direct looping and insulated neighborhood data. A subset of these landscapes contains an exceptional amount of transcriptional apparatus, reminiscent of SEs (3), so we term this subset 3D-SEs. Well-characterized oncogenes, including c-Myc, acquire 3D-SEs in tumor cells where a c-Myc¬-associated linear SE was not identified, suggesting SE acquisition by c-Myc and other oncogenes has been underestimated. Each gene's regulatory network can also surprisingly extend beyond the confines of insulated neighborhoods and incorporate additional distal enhancers. Visualizing instances of 3D-SEs with microscopy demonstrates that they are components of liquid-liquid phase-separated bodies in cells, suggesting gene regulatory landscapes underpin these transcriptional condensates. The interactions comprising gene regulatory networks and their target genes thus extend previous interpretations of the targets of enhancers, signaling pathways, and disease-associated enhancer variants. References: 1. Hnisz, Abraham, Lee, et al. and Young, Cell 2013. 2. Mansour, Abraham, et al. and Young and Look, Science 2014. 3. Whyte, Orlando, Hnisz, Abraham, et al. and Young, Cell 2013. Citation Format: Brian J. Abraham, Yang Eric Guo, Denes Hnisz, Charles H. Li, Abraham S. Weintraub, Daniel S. Day, Jurian Schuijers, Tong Ihn Lee, Richard A. Young. Three-dimensional gene regulatory landscapes in normal and cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 971.
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- 2018
10. YY1 Is a Structural Regulator of Enhancer-Promoter Loops
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Nathanael S. Gray, James E. Bradner, Yang Eric Guo, Brian J. Abraham, Richard A. Young, Dennis L. Buckley, Abraham S. Weintraub, Behnam Nabet, Alla A. Sigova, Rudolf Jaenisch, Charles H. Li, Denes Hnisz, Alicia V. Zamudio, Daniel S. Day, Nancy M. Hannett, Malkiel A. Cohen, Massachusetts Institute of Technology. Department of Biology, Weintraub, Abraham Selby, Li, Charles Han, Zamudio Montes de Oca, Alicia, Jaenisch, Rudolf, and Young, Richard A
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0301 basic medicine ,Regulation of gene expression ,CCCTC-Binding Factor ,YY1 ,Promoter ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Enhancer Elements, Genetic ,030104 developmental biology ,chemistry ,CTCF ,embryonic structures ,Animals ,Humans ,Promoter Regions, Genetic ,Enhancer ,Transcription factor ,Gene ,Embryonic Stem Cells ,YY1 Transcription Factor ,DNA - Abstract
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control. YY1 is a structural regulator of enhancer-promoter interactions and facilitates gene expression., National Institutes of Health (U.S.) (Grant HG002668/GM123511), National Institutes of Health (U.S.) (Grant R37HD045022/R01-NS088538/R01-MH104610), Virginia and Daniel K. Ludwig Graduate Fellowship, National Science Foundation (U.S.). Graduate Research Fellowship Program
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- 2017
11. 3D Chromosome Regulatory Landscape of Human Pluripotent Cells
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Diego Borges-Rivera, Gianluca Pegoraro, Tong Ihn Lee, Abraham S. Weintraub, Zi Peng Fan, Tom Misteli, Benjamin E. Powell, Denes Hnisz, Rudolf Jaenisch, Richard A. Young, Sigal Shachar, Daniel B. Dadon, Xiong Ji, Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Dadon, Daniel Benjamin, Fan, Zi Peng, Borges-Rivera, Diego Ramon, Weintraub, Abraham Selby, Jaenisch, Rudolf, and Young, Richard A
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Pluripotent Stem Cells ,0301 basic medicine ,CCCTC-Binding Factor ,Chromosomal Proteins, Non-Histone ,Human Embryonic Stem Cells ,Cell Cycle Proteins ,Context (language use) ,Computational biology ,Biology ,Cell Line ,03 medical and health sciences ,Genetics ,Chromosomes, Human ,Humans ,Disease ,Induced pluripotent stem cell ,Enhancer ,Regulation of gene expression ,Cohesin ,DNA ,Cell Biology ,Embryonic stem cell ,Chromatin ,Repressor Proteins ,MicroRNAs ,Enhancer Elements, Genetic ,030104 developmental biology ,Gene Expression Regulation ,CTCF ,Nucleic Acid Conformation ,Molecular Medicine ,Insulator Elements ,Transcription Factors - Abstract
In this study, we describe the 3D chromosome regulatory landscape of human naive and primed embryonic stem cells. To devise this map, we identified transcriptional enhancers and insulators in these cells and placed them within the context of cohesin-associated CTCF-CTCF loops using cohesin ChIA-PET data. The CTCF-CTCF loops we identified form a chromosomal framework of insulated neighborhoods, which in turn form topologically associating domains (TADs) that are largely preserved during the transition between the naive and primed states. Regulatory changes in enhancer-promoter interactions occur within insulated neighborhoods during cell state transition. The CTCF anchor regions we identified are conserved across species, influence gene expression, and are a frequent site of mutations in cancer cells, underscoring their functional importance in cellular regulation. These 3D regulatory maps of human pluripotent cells therefore provide a foundation for future interrogation of the relationships between chromosome structure and gene control in development and disease., Center for Cancer Research (National Cancer Institute (U.S.)), National Institutes of Health (U.S.). Intramural Research Program, Virginia and Daniel K. Ludwig Graduate Fellowship, National Institutes of Health (U.S.) (Grants HG002668 and HD 045022), Simons Foundation (Grant SFLIFE 286977)
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- 2015
12. Abstract 5488: APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL
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Zhaodong Li, Richard A. Young, Theresa E. Leon, Takaomi Sanda, Alla Berezovskaya, Shuhong Shen, Adele K. Fielding, Brian J. Abraham, Thomas Look, Nadine Farah, Shi Hao Tan, Benshang Li, Jinghui Zhang, Abraham S. Weintraub, Yu Liu, and Marc R. Mansour
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APOBEC ,Genetics ,Cancer Research ,Oncology ,Mutation (genetic algorithm) ,Biology ,Enhancer ,Signature (topology) - Abstract
Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells resulting in clonal selection. Although most cancer causing mutations have been detected in the protein-coding regions of the cancer genome, driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well. Citation Format: Zhaodong Li, Brian Abraham, Alla Berezovskaya, Nadine Farah, Yu Liu, Theresa Leon, Adele Fielding, Shi Hao Tan, Takaomi Sanda, Abraham Weintraub, Benshang Li, Shuhong Shen, Jinghui Zhang, Marc Mansour, Richard Young, Thomas Look. APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5488. doi:10.1158/1538-7445.AM2017-5488
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- 2017
13. Correction: Corrigendum: Small genomic insertions form enhancers that misregulate oncogenes
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Richard A. Young, Nicholas Kwiatkowski, Benshang Li, Julia Etchin, Abraham S. Weintraub, A. Thomas Look, Yu Liu, Nina Weichert-Leahey, Charles H. Li, Denes Hnisz, Jinghui Zhang, Shuhong Shen, Marc R. Mansour, Zhaodong Li, Brian J. Abraham, Tong Ihn Lee, and Sunniyat Rahman
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0301 basic medicine ,Supplementary data ,Multidisciplinary ,Computer science ,Published Erratum ,Science ,MEDLINE ,General Physics and Astronomy ,General Chemistry ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,Enhancer - Abstract
Nature Communications 8: Article number:14385 (2017); Published: 9 February 2017; Updated: 1 June 2017 In the original version of Supplementary Data 1 associated with this Article, the list of predicted enhancer-associated insertions was inadvertently truncated. The HTML has now been updated to include the correct version of the Supplementary Data 1.
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- 2017
14. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers
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Brian J. Abraham, Charles Y. Lin, Abraham S. Weintraub, Richard A. Young, Jurian Schuijers, Denes Hnisz, Tong Ihn Lee, James E. Bradner, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Weintraub, Abraham Selby, and Young, Richard A
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Biology ,medicine.disease_cause ,Article ,Cell Line ,Mice ,Super-enhancer ,Neoplasms ,medicine ,Animals ,Humans ,Enhancer ,Molecular Biology ,Transcription factor ,Embryonic Stem Cells ,Regulation of gene expression ,Genetics ,HEK 293 cells ,Gene Expression Regulation, Developmental ,Cell Biology ,HCT116 Cells ,Embryonic stem cell ,Cell biology ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,HEK293 Cells ,Signal transduction ,Carcinogenesis ,Signal Transduction ,Transcription Factors - Abstract
Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis., National Institutes of Health (U.S.) (Grant HG002668)
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- 2014
15. Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes
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Tong Ihn Lee, Gang Ren, Denes Hnisz, Lyndon Nuoxi Zhang, Abraham S. Weintraub, Jill M. Dowen, Richard A. Young, Keji Zhao, Jurian Schuijers, Brian J. Abraham, Zi Peng Fan, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Zhang, Lyndon Nuoxi, and Young, Richard A
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Pluripotent Stem Cells ,CCCTC-Binding Factor ,Chromatin Immunoprecipitation ,Chromosomal Proteins, Non-Histone ,Cell Cycle Proteins ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Super-enhancer ,Animals ,Induced pluripotent stem cell ,Gene ,Embryonic Stem Cells ,030304 developmental biology ,Genetics ,0303 health sciences ,Cohesin ,Biochemistry, Genetics and Molecular Biology(all) ,High-Throughput Nucleotide Sequencing ,Chromosome ,Sequence Analysis, DNA ,Chromosomes, Mammalian ,Embryonic stem cell ,Repressor Proteins ,Organ Specificity ,CTCF ,030217 neurology & neurosurgery - Abstract
The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of genes that control cell identity and repression of genes encoding lineage-specifying developmental regulators. Here, we use ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome. The results produce a map of enhancer-promoter interactions and reveal that super-enhancer-driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by cohesin. These looped structures form insulated neighborhoods whose integrity is important for proper expression of local genes. We also find that repressed genes encoding lineage-specifying developmental regulators occur within insulated neighborhoods. These results provide insights into the relationship between transcriptional control of cell identity genes and control of local chromosome structure., National Institutes of Health (U.S.) (Grant HG002668)
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- 2014
16. Abstract 2004: Nucleation of transcriptional super-enhancers at tumor oncogenes by small insertions
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Marc R. Mansour, Brian J. Abraham, Sunniyat Rahman, Abraham S. Weintraub, Zhaodong Li, Nicholas Kwiatkowski, Richard A. Young, A. Thomas Look, Tong Ihn Lee, Charles H. Li, and Denes Hnisz
- Subjects
Genetics ,Cancer Research ,Cancer ,Biology ,medicine.disease ,Genome ,DNA sequencing ,Oncology ,medicine ,Epigenetics ,Binding site ,Enhancer ,Transcription factor ,TAL1 - Abstract
Transcriptional super-enhancers drive expression of oncogenes in many cancers and are being targeted with novel transcriptional and epigenetic therapeutics[1,2,3,4]. Super-enhancers are acquired by cancers through multiple mechanisms, including DNA translocation of an extant super-enhancer and focal amplification. We recently discovered a novel mechanism by which super-enhancers are nucleated in T cell acute lymphoblastic leukemias (T-ALLs)[5]. In this case, a small, monoallelic insertion creates a DNA binding site for a master transcription factor protein, which binds and recruits additional factors to nucleate the super-enhancer, which in turn drives high levels of the TAL1 oncogene. We describe here a method for unbiased identification of similar genomic insertions that nucleate potentially oncogenic regulatory elements in cancers. This approach uses data from genome-wide ChIP-Seq studies that map locations of enhancer-binding proteins to identify short DNA sequences missing from reference genomes. We have found and catalogued many additional genomic insertions in 80 additional cancers. An additional insertion has been functionally characterized and determined to be a bona fide enhancer-nucleating insertion that exists in patient genomes. I will describe new insights into the regulation of cancer that occur due to nucleation of novel regulatory elements. [1] Hnisz, Abraham, Lee, et al., Cell 2013 [2] Loven, Hoke, Lin, et al., Cell 2013 [3] Kwiatkowski, et al., Nature, 2014 [4] Wang, et al., Cell, 2015 [5] Mansour et al., Science 2014 Citation Format: Brian J. Abraham, Denes Hnisz, Abraham S. Weintraub, Nicholas Kwiatkowski, Charles H. Li, Sunniyat Rahman, Zhaodong Li, Tong Ihn Lee, A Thomas Look, Marc Mansour, Richard A. Young. Nucleation of transcriptional super-enhancers at tumor oncogenes by small insertions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2004.
- Published
- 2016
17. Abstract A44: The role of PHF6 in maintaining pre-B cell commitment in B-cell acute lymphoblastic leukemia
- Author
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Michael T. Hemann, Tyler Jacks, Yunpeng Liu, Francisco J. Sánchez-Rivera, Richard A. Young, Abraham S. Weintraub, Yadira M. Soto-Feliciano, Arjun Bhutkar, and Jordan M. E. Bartlebaugh
- Subjects
Genetics ,Cancer Research ,Transdifferentiation ,Biology ,Chromatin ,medicine.anatomical_structure ,Oncology ,TCF3 ,Cancer research ,medicine ,H3K4me3 ,Epigenetics ,Transcription factor ,Chromatin immunoprecipitation ,B cell - Abstract
Loss of function mutations in the plant homeodomain factor 6 (PHF6) are responsible for the Börjeson–Forssman–Lehmann syndrome, a familial X-linked intellectual disability disorder, and are observed in approximately 20% of adult T-cell acute lymphoblastic leukemias (T-ALLs) and 3% of adult acute myeloid leukemias (AMLs). However, mutations in B-cell lineage malignancies are notably absent. Interestingly, our recent work has uncovered PHF6 as a positive growth regulator in B-cell acute lymphoblastic leukemia (B-ALL) through a genome-scale in vivo loss-of-function screen. To identify the molecular mechanism by which PHF6 acts to promote B-ALL growth in vivo, we utilized CRISPR-Cas9 to delete Phf6 in murine B-ALL cells. Transplantation of Phf6 knockout cells (Phf6KO) into immunocompetent syngeneic recipients significantly extends disease latency and survival, therefore validating PHF6 as a bona fide positive growth regulator of B-ALL in vivo. Strikingly, these mice develop lymphoma-like disease with complete penetrance, characterized by significantly enlarged lymph nodes, decreased disease burden in the spleen and increased expression of the canonical T-cell marker CD4, suggesting that Phf6KO B-ALL cells transdifferentiated to cells resembling those of the T-cell lineage. To dissect the mechanism by which PHF6 regulates this lineage decision, we carried out a combination of RNA sequencing and chromatin immunoprecipitation (ChIP) analyses in Phf6WT and Phf6KO cells. RNA sequencing analysis revealed many differentially expressed genes in Phf6KO B-ALL cells , including gene sets involved in pathways important for B-cell development. ChIP-sequencing analysis of PHF6 and several histone marks (H3K27Ac, H3K27me3, H3K4me3) in Phf6WT B-ALL cells revealed that PHF6 and H3K27Ac signals co-localize close to the transcription start site of a significant proportion of differentially expressed genes. Transcription factor binding motif analysis revealed significant enrichment for several well-described master regulators of B-cell development, including PU.1, EGR-1, EBF-1, NF-κB and TCF3/TCF12. Notably, a number of these predicted transcription factors co-immunoprecipitated with PHF6 in Phf6WT B-ALL cells. These findings reveal an essential role for PHF6 in the maintenance of B-cell identity in B-ALL by activating, directly or indirectly, genes that are crucial for B-cell lineage commitment. Collectively, these results indicate that loss-of-function of PHF6 in B-ALL leads to transdifferentiation to the T-cell lineage, potentially explaining the apparent absence of PHF6 mutations in human B cell-lineage malignancies. Citation Format: Yadira M. Soto-Feliciano, Jordan ME Bartlebaugh, Yunpeng Liu, Francisco J. Sánchez-Rivera, Abraham S. Weintraub, Arjun Bhutkar, Tyler E. Jacks, Richard A. Young, Michael T. Hemann. The role of PHF6 in maintaining pre-B cell commitment in B-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A44.
- Published
- 2016
18. Abstract PR06: Nucleation of transcriptional super-enhancers at tumor oncogenes
- Author
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Denes Hnisz, Richard A. Young, Nancy M. Hannett, Brian J. Abraham, Abraham S. Weintraub, and Nicholas Kwiatkowski
- Subjects
Genetics ,Cancer Research ,Systems biology ,Cell ,Cancer ,Biology ,medicine.disease ,Genome ,medicine.anatomical_structure ,Oncology ,medicine ,Epigenetics ,Enhancer ,Transcription factor ,TAL1 - Abstract
Transcriptional super-enhancers drive expression of oncogenes in many cancers and are being targeted with novel transcriptional and epigenetic therapeutics (1,2,3,4). Super-enhancers are acquired in cancers through multiple mechanisms, including DNA translocation of an extant super-enhancer and focal amplification. We recently discovered a novel mechanism by which super-enhancers are nucleated in T cell acute lymphoblastic leukemias (T-ALLs) (5). In this case, a small, monoallelic insertion creates a DNA binding site for a master transcription factor protein, which binds and recruits additional factors to nucleate the super-enhancer, which in turn drives high levels of the TAL1 transcription factor. We describe here a method for unbiased identification of similar genomic insertions that nucleate potentially oncogenic regulatory elements in cancers. This approach uses data from genome-wide ChIP-Seq studies that map locations of enhancer-binding proteins to identify sequences missing from reference genomes. We have found many additional genomic insertions in many additional cancers. I will describe new insights into the regulation of cancer that occur due to nucleation of novel regulatory elements. 1 Hnisz, Abraham, Lee, et al., Cell 2013 2 Loven, Hoke, Lin, et al., Cell 2013 3 Kwiatkowski, et al., Nature, 2014 4 Chipumoro, et al., Cell, 2014 5 Mansour et al., Science 2014 Citation Format: Brian J. Abraham, Nicholas Kwiatkowski, Abraham S. Weintraub, Denes Hnisz, Nancy Hannett, Richard A. Young. Nucleation of transcriptional super-enhancers at tumor oncogenes. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR06.
- Published
- 2015
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