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Abraham S. Weintraub

Bio: Abraham S. Weintraub is an academic researcher from Massachusetts Institute of Technology. The author has contributed to research in topics: Enhancer & Gene. The author has an hindex of 16, co-authored 25 publications receiving 4544 citations.

Papers
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Journal ArticleDOI
25 Mar 2016-Science
TL;DR: Insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) are mapped and it is found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.
Abstract: Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.

800 citations

Journal ArticleDOI
09 Oct 2014-Cell
TL;DR: Using ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome produces a map of enhancer-promoter interactions and reveals 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.

730 citations

Journal ArticleDOI
14 Dec 2017-Cell
TL;DR: It is shown 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.

654 citations

01 Oct 2014
TL;DR: In this article, the authors used ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome 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 co-hesin.
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.

603 citations

01 Nov 2015
TL;DR: Wala et al. as discussed by the authors investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells.
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 Disrupting the boundaries between three-dimensional neighborhoods in the genome can activate cancer-promoting genes. [Also see Perspective by Wala and Beroukim] Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.

553 citations


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Journal ArticleDOI
27 Jul 2018-Science
TL;DR: It is postulated that super-enhancers are phase-separated multimolecular assemblies, also known as biomolecular condensates, which provide a means to compartmentalize and concentrate biochemical reactions within cells.
Abstract: Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.

1,506 citations

Journal ArticleDOI
18 May 2017-Cell
TL;DR: The data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading, and provides new fundamental insights into the rules governing mammalian genome organization.

1,259 citations

Journal ArticleDOI
TL;DR: The 3DEpiLoop algorithm predicts three-dimensional chromatin looping interactions within topologically associating domains (TADs) from one-dimensional epigenomics and transcription factor profiles using the statistical learning.
Abstract: This study aims to understand through statistical learning the basic biophysical mechanisms behind three-dimensional folding of epigenomes. The 3DEpiLoop algorithm predicts three-dimensional chromatin looping interactions within topologically associating domains (TADs) from one-dimensional epigenomics and transcription factor profiles using the statistical learning. The predictions obtained by 3DEpiLoop are highly consistent with the reported experimental interactions. The complex signatures of epigenomic and transcription factors within the physically interacting chromatin regions (anchors) are similar across all genomic scales: genomic domains, chromosomal territories, cell types, and different individuals. We report the most important epigenetic and transcription factor features used for interaction identification either shared, or unique for each of sixteen (16) cell lines. The analysis shows that CTCF interaction anchors are enriched by transcription factors yet deficient in histone modifications, while the opposite is true in the case of RNAP II mediated interactions. The code is available at the repository https://bitbucket.org/4dnucleome/3depiloop .

1,241 citations

Journal ArticleDOI
23 Mar 2017-Cell
TL;DR: In this paper, a phase separation model was proposed to explain established and recently described features of transcriptional control, such as the formation of super-enhancers, the sensitivity of superenhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes.

1,162 citations

Journal ArticleDOI
13 Dec 2018-Cell
TL;DR: It is reported that diverse ADs form phase- separated condensates with the Mediator coactivator, suggesting that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensate with Mediation is involved in gene activation.

1,040 citations