Enhancer RNAs and regulated transcriptional programs

Lam, Michael Tun Yin; Li, Wenbo; Rosenfeld, Michael G.; Glass, Christopher K.

doi:10.1016/j.tibs.2014.02.007

Cited by 467 publications

(440 citation statements)

References 89 publications

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“…Recent studies have demonstrated that AEs physically interact with promoters to form enhancer-promoter loops (15). In addition, RNA polymerase II (Pol II) binds to AEs and transcribes enhancer DNAs into enhancer RNAs (eRNAs) (16). Consistent with the Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) data obtained from a previous study (12), Chromatin Conformation Capture (3C) assays confirmed that MLL4 + AEs formed loops with promoters on Nanog and Lefty1 loci.…”

Section: Mll4 Is Dispensable For Maintaining Esc Identity Gene Expresmentioning

confidence: 99%

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Wang

Lee

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

192

188

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Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.enhancer | MLL4/KMT2D | H3K4 methyltransferase | cell fate transition | p300 I n mammalian cells, enhancers coordinate with promoters to precisely control cell-type-specific gene transcription, which determines the cell identity (1, 2). Comprehensive genome-wide studies have provided insights into the chromatin signatures of enhancers. Primed enhancers are marked by H3K4me1/2. Active enhancers (AEs) are further marked by the histone acetyltransferases CBP/p300-mediated H3K27ac (3). Recent studies classify AEs into typical enhancers and superenhancers. Superenhancers are clusters of AEs bound by lineage-determining transcription factors (TFs). Compared with typical enhancers, superenhancers are more cell-lineage-specific and control cell identity (4). Enhancer activation is orchestrated through a regulatory network involving lineage-determining TFs and chromatinmodifying complexes (2). However, how chromatin-modifying complexes regulate enhancer activation and cell fate transition is poorly understood.Embryonic stem cells (ESCs) derived from blastocysts are capable of unlimited replication in vitro, a property known as ESC self-renewal. ESC identity is maintained during self-renewal. ESC self-renewal is controlled by a core circuitry of TFs including Oct4, Sox2, and Nanog (4). ESCs can rapidly respond to environmental cues and differentiate into three germ layers-ectoderm, endoderm, and mesoderm-which consist of all cell lineages within days (5). Differentiated somatic cells can also be converted back to the pluripotent stage by ectopic expression of Oct4 and Sox2 together with Klf4 and c-Myc, a process known as somatic cell reprogramming into induced pluripotent stem cells (iPSCs) (6). The dramatic changes of ce...

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Section: Mll4 Is Dispensable For Maintaining Esc Identity Gene Expresmentioning

confidence: 99%

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Wang

Lee

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

192

188

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“…25 Finally, emerging data suggests enhancer RNAs play a role in regulation of gene expression. [26][27][28] Further characterization of the endogenous super-enhancers by ChIP-seq will identify potential key genes that control Merkel cell state, key oncogenes/tumor suppressor genes that function in the acquisition of hallmark capabilities in MCC tumorigenesis, and biomarkers to direct the treatment.…”

Section: Disruption Of Brd4 At the Putative C-myc Super-enhancer Regimentioning

confidence: 99%

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

et al. 2015

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“…Interestingly, previous genomic studies have shown that active enhancers overlap with RNA Pol II loading, which generates active bidirectional transcripts called enhancer RNAs (eRNAs) (10,(17)(18)(19). Although the role of enhancer transcription remains unknown, it is considered a hallmark of functionally active enhancers (20)(21)(22)(23)(24).…”

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confidence: 99%

“…It has also been strongly implicated that eRNAs and enhancer functions are involved in the regulation of inflammatory transcription networks (22,(34)(35)(36)(37); however, it remains to be solved how, and if at all, SE-associated eRNAs (seRNAs) contribute to the regulatory landscape. Using global nuclear run-on sequencing (GRO-Seq) to map the location and orientation of all active RNA polymerases genome-wide (38), we found eRNAs extensively transcribed within the macrophage SE subset.…”

mentioning

confidence: 99%

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

Hah

Benner

Chong³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

149

138

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Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global nuclear run-on sequencing are extensively transcribed within super enhancers and are dynamically regulated in response to cellular signaling. Using Toll-like receptor 4 (TLR4) signaling in macrophages as a model system, we find that transcription of super enhancer-associated eRNAs is dynamically induced at most of the key genes driving innate immunity and inflammation. Unexpectedly, genes repressed by TLR4 signaling are also associated with super enhancer domains and accompanied by massive repression of eRNA transcription. Furthermore, we find each super enhancer acts as a single regulatory unit within which eRNA and genic transcripts are coordinately regulated. The key regulatory activity of these domains is further supported by the finding that super enhancer-associated transcription factor binding is twice as likely to be conserved between human and mouse than typical enhancer sites. Our study suggests that transcriptional activities at super enhancers are critical components to understand the dynamic gene regulatory network.super enhancers | enhancer RNAs | transcription factors | GRO-Seq | macrophage

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Enhancer RNAs and regulated transcriptional programs

Cited by 467 publications

References 89 publications

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs

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