Initiating RNA Polymerase II and TIPs as hallmarks of enhancer activity and tissue-specificity

Koch, Frank‐Thomas; Andrau, Jean-Christophe

doi:10.4161/trns.2.6.18747

Cited by 34 publications

(28 citation statements)

References 25 publications

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“…Recent studies have also shown that enhancers themselves are broadly transcribed, resulting in the production of enhancer-derived RNAs (eRNAs) (De Santa et al, 2010; Kim et al, 2010; Koch and Andrau, 2011; Lam et al, 2014). Given that transcription is generally associated with H3K4me3 (Vermeulen et al, 2007; Wysocka et al, 2006), we therefore wished to determine whether the switch from H3K4me1 to H3K4me3 in the absence of RACK7 also influenced local transcription of eRNAs at target enhancers.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Shen

Guo

et al. 2016

Cell

146

193

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Summary Regulation of enhancer activity is important for controlling gene expression programs. Here we report that a biochemical complex that contains a potential chromatin reader, RACK7 and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Shen

Guo

et al. 2016

Cell

146

193

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“…This relies on the assumption that in vitro (nuclear run-on) determination of the activity of RNA polymerases (RNAPs) is a reliable indicator of transcriptional activation. This has been proven in other systems and leads to the identification of active enhancers in other cell types (Koch and Andrau 2011;Wang et al 2011;Bonn et al 2012), although systematic comparisons or crossvalidation with other methods such as subcellular RNA fractionation (Bhatt et al 2012) has not been done. The usage of GRO-seq for the determination of direct transcriptional responses has two major advantages: (1) The dynamics of the nascent RNA levels depends only on the rate of RNAP activity, and therefore it is matching the expected time course of a directly regulated gene.…”

Section: Discussionmentioning

confidence: 99%

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages

et al. 2014

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RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program.

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“…Enhancers have recently been defined as discrete genomic sites harboring a local combination of open chromatin structure (hypersensitivity to DNAse I), specific covalent histone modifications like mono-and di-methylation of histone 3 lysine 4 (H3K4me1, H3K4me2), acetylation of H3K27, low levels of H3K4me3, and RNA polymerase II (RNAP II) and transcription factor (TF) occupancy. [1][2][3] Based on this epigenetic definition, thousands of potential enhancers were localized genome-wide, some of which have been functionally validated in vivo. 4 current dominant model for long-range transcriptional regulation proposes that distal enhancers are brought into physical proximity to their target genes in the threedimensional nuclear space by chromatin looping mechanisms.…”

Section: Transcription Regulation By Distal Enhancersmentioning

confidence: 99%

Transcription regulation by distal enhancers

et al. 2012

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G enome-wide chromatin profiling efforts have shown that enhancers are often located at large distances from gene promoters within the non-coding genome. Whereas enhancers can stimulate transcription initiation by communicating with promoters via chromatin looping mechanisms, we propose that enhancers may also stimulate transcription elongation by physical interactions with intronic elements. We review here recent findings derived from the study of the hematopoietic system. IntroductionThe development of multicellular organisms relies upon the capacity of stem and progenitor cells to respond to their microenvironment and differentiate upon exposure to specific stimuli. This multi-step process involves complex epigenetic changes within regulatory transcriptional networks, which contribute to the timely activation and repression of key developmental genes. Transcription of mammalian genes relies on the presence of a variety of cis-DNA regulatory sequences such as promoters and enhancers. Whereas gene promoters can be relatively easy to identify (i.e., at the 5' end of transcriptional units), locating and characterizing enhancers is far more complicated. Transgenic experiments carried out over the last few decades have taught us important lessons about transcriptional enhancers and genomic organization. Attempts to express transgenes in animals, under the control of endogenous promoter sequences, often resulted in weak

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Initiating RNA Polymerase II and TIPs as hallmarks of enhancer activity and tissue-specificity

Cited by 34 publications

References 25 publications

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages

Transcription regulation by distal enhancers

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