Identification of H3K4me1-associated proteins at mammalian enhancers

Nature Genetics, Год журнала: 2017, Номер 50(1), С. 73 - 82

Опубликована: Дек. 17, 2017

Язык: Английский

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H3K4me3 regulates RNA polymerase II promoter-proximal pause-release

Nature, Год журнала: 2023, Номер 615(7951), С. 339 - 348

Опубликована: Март 1, 2023

Abstract Trimethylation of histone H3 lysine 4 (H3K4me3) is associated with transcriptional start sites and has been proposed to regulate transcription initiation 1,2 . However, redundant functions the H3K4 SET1/COMPASS methyltransferase complexes complicate elucidation specific role H3K4me3 in regulation 3,4 Here, using mouse embryonic stem cells as a model system, we show that acute ablation shared subunits leads complete loss all methylation. Turnover occurs more rapidly than H3K4me1 H3K4me2 dependent on KDM5 demethylases. Notably, does not have detectable effects but widespread decrease output, an increase RNA polymerase II (RNAPII) pausing slower elongation. We required for recruitment integrator complex subunit 11 (INTS11), which essential eviction paused RNAPII Thus, our study demonstrates distinct pause-release elongation rather initiation.

Язык: Английский

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dCas9-based epigenome editing suggests acquisition of histone methylation is not sufficient for target gene repression

Nucleic Acids Research, Год журнала: 2017, Номер 45(17), С. 9901 - 9916

Опубликована: Июнь 28, 2017

Distinct epigenomic profiles of histone marks have been associated with gene expression, but questions regarding the causal relationship remain. Here we investigated activity a broad collection genomically targeted epigenetic regulators that could write repressed chromatin state (G9A, SUV39H1, Krüppel-associated box (KRAB), DNMT3A as well first targetable versions Ezh2 and Friend GATA-1 (FOG1)). dCas9 fusions produced target repression over range 0- to 10-fold varied by locus cell type. dCpf1 were unable repress expression. The most persistent required action several effector domains; however, KRAB-dCas9 did not contribute persistence in contrast previous reports. A 'direct tethering' strategy attaching methyltransferase enzyme dCas9, 'recruitment' N-terminal 45 residues FOG1 recruit endogenous nucleosome remodeling deacetylase complex, both successful deposition H3K27me3. Surprisingly, was correlated either H3K9me3 or Our results suggest so-called repressive modifications are sufficient for repression. easily programmable toolkit allowed precise control information dissection between epigenome regulation.

Язык: Английский

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Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability

Nature Genetics, Год журнала: 2017, Номер 49(11), С. 1647 - 1653

Опубликована: Окт. 2, 2017

Язык: Английский

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Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Окт. 8, 2019

Enhancer RNA (eRNA) is a type of noncoding transcribed from the enhancer. Although critical roles eRNA in gene transcription control have been increasingly realized, systemic landscape and potential function eRNAs cancer remains largely unexplored. Here, we report integration multi-omics pharmacogenomics data across large-scale patient samples cell lines. We observe cancer-/lineage-specificity eRNAs, which may be driven by tissue-specific TFs. are involved multiple signaling pathways through putatively regulating their target genes, including clinically actionable genes immune checkpoints. They also affect drug response within-pathway or cross-pathway means. characterize oncogenic therapeutic liability one eRNA, NET1e, supporting clinical feasibility eRNA-targeted therapy. identify panel relevant developed user-friendly portal. Our study reveals transcriptional utility cancer.

Язык: Английский

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Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation

Genes & Development, Год журнала: 2018, Номер 32(3-4), С. 202 - 223

Опубликована: Фев. 1, 2018

Enhancers are important genomic regulatory elements directing cell type-specific transcription. They assume a key role during development and disease, their identification functional characterization have long been the focus of scientific interest. The advent next-generation sequencing clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-based genome editing has revolutionized means by which we study enhancer biology. In this review, cover recent developments in prediction enhancers based on chromatin characteristics reporter assays endogenous DNA perturbations. We discuss that two latter approaches provide different complementary insights, especially assessing sufficiency necessity for transcription activation. Furthermore, insights into mechanistic aspects function, including findings about cofactor requirements post-translational histone modifications such as monomethylation H3 Lys4 (H3K4me1). Finally, survey how these advance our understanding regulation with respect to promoter specificity transcriptional bursting an outlook covering open questions promising developments.

Язык: Английский

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A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription

Molecular Cell, Год журнала: 2017, Номер 67(2), С. 308 - 321.e6

Опубликована: Июль 1, 2017

Язык: Английский

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KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

Cancer Cell, Год журнала: 2020, Номер 37(4), С. 599 - 617.e7

Опубликована: Апрель 1, 2020

Язык: Английский

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Evaluating Enhancer Function and Transcription

Annual Review of Biochemistry, Год журнала: 2020, Номер 89(1), С. 213 - 234

Опубликована: Март 20, 2020

Cell-type- and condition-specific profiles of gene expression require coordination between protein-coding promoters cis-regulatory sequences called enhancers. Enhancers can stimulate activity at great genomic distances from their targets, raising questions about how enhancers communicate with specific what molecular mechanisms underlie enhancer function. Characterization loci has identified the features active that accompany binding transcription factors local opening chromatin. These characteristics include coactivator recruitment, histone modifications, noncoding RNA transcription. However, it remains unclear which these functionally contribute to activity. Here, we discuss is known regulate target genes communicate. Further, describe recent data demonstrating many similarities they control, highlight unanswered in field, such as potential roles

Язык: Английский

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Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate

Frontiers in Cell and Developmental Biology, Год журнала: 2020, Номер 7

Опубликована: Янв. 13, 2020

Enhancers are cis-regulatory elements that cooperate with promoters to control target gene transcription. Unlike promoters, enhancers not necessarily adjacent genes and can exert their functions regardless of enhancer orientations, positions spatial segregations from genes. Thus, for a long time, the question as how act in temporal manner attracted considerable attention. The recent discovery also actively abundantly transcribed raises interesting questions about exact roles RNA (eRNA) regulation. In this review, we highlight process transcription diverse features eRNA. We review evidence eRNA functions, which include enhancer-promoter looping, chromatin modifying, regulating. As active enhancers, they exhibit tissue lineage specificity, serve markers cell state function. Finally, discuss unique relationship between super phase separation wherein may contribute significantly fate decisions.

Язык: Английский

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