Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development

Bonn, Stefan; Zinzen, Robert P.; Girardot, Charles; Gustafson, E. Hilary; Perez‐Gonzalez, Alexis; Delhomme, Nicolas; Ghavi-Helm, Yad; Wilczyński, Bartek; Riddell, Andrew; Furlong, Eileen E. M.

doi:10.1038/ng.1064

Cited by 465 publications

(560 citation statements)

References 69 publications

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“…Despite the variance, however, there was a significant trend for enhancers to have higher H3K27me3 levels in the uninduced versus active state (P < 10 −2 , Wilcoxon rank-sum test) (Fig. 3B), consistent with previous findings (Bonn et al 2012).…”

Section: H3k27me3 Is Not a Good Marker For Uninduced Enhancers Or Seqsupporting

confidence: 90%

“…Most open enhancer regions are marked by histone monomethylation on lysine 4 of histone H3 (H3K4me1), but only active enhancers carry lysine 27 acetylation on histone H3 (H3K27ac) (Creyghton et al 2010;Ernst et al 2011;Rada-Iglesias et al 2011;Zentner et al 2011;Bonn et al 2012). Since some inactive enhancers show activation during later development, the combination of H3K4me1 along with low H3K27ac at inactive enhancers was termed the poised enhancer signature (Creyghton et al 2010;Rada-Iglesias et al 2011).…”

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confidence: 99%

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Drosophilapoised enhancers are generated during tissue patterning with the help of repression

Koenecke

Johnston

et al. 2016

Preprint

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Histone modifications are frequently used as markers for enhancer states, but how to interpret enhancer states in the context of embryonic development is not clear. The poised enhancer signature, involving H3K4me1 and low levels of H3K27ac, has been reported to mark inactive enhancers that are poised for future activation. However, future activation is not always observed, and alternative reasons for the widespread occurrence of this enhancer signature have not been investigated. By analyzing enhancers during dorsal-ventral (DV) axis formation in the Drosophila embryo, we find that the poised enhancer signature is specifically generated during patterning in the tissue where the enhancers are not induced, including at enhancers that are known to be repressed by a transcriptional repressor. These results suggest that, rather than serving exclusively as an intermediate step before future activation, the poised enhancer state may be a mark for spatial regulation during tissue patterning. We discuss the possibility that the poised enhancer state is more generally the result of repression by transcriptional repressors.

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Section: H3k27me3 Is Not a Good Marker For Uninduced Enhancers Or Seqsupporting

confidence: 90%

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confidence: 99%

Drosophilapoised enhancers are generated during tissue patterning with the help of repression

Koenecke

Johnston

et al. 2016

Preprint

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“…The increase of DNA methylation in CpG sites located in the enhancer regions is particularly striking because enhancer activity is known to be anticorrelated with DNA methylation and is highly cell type-specific (Heintzman et al 2009;Stadler et al 2011;Bonn et al 2012). We have also previously shown that repressed genes may have permissive enhancers that can initiate cell-fate reprogramming in fibroblasts (Taberlay et al 2011), but what we observe in the intestinal epithelium illustrates another side in the complex regulation of cell identity.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of the human intestinal epigenome by surgical tissue transposition

et al. 2014

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Extracellular cues play critical roles in the establishment of the epigenome during development and may also contribute to epigenetic perturbations found in disease states. The direct role of the local tissue environment on the post-development human epigenome, however, remains unclear due to limitations in studies of human subjects. Here, we use an isogenic human ileal neobladder surgical model and compare global DNA methylation levels of intestinal epithelial cells pre-and post-neobladder construction using the Infinium HumanMethylation450 BeadChip. Our study is the first to quantify the effect of environmental cues on the human epigenome and show that the local tissue environment directly modulates DNA methylation patterns in normal differentiated cells in vivo. In the neobladder, the intestinal epithelial cells lose their tissue-specific epigenetic landscape in a time-dependent manner following the tissue's exposure to a bladder environment. We find that de novo methylation of many intestine-specific enhancers occurs at the rate of 0.41% per month (P < 0.01, Pearson = 0.71), while demethylation of primarily non-intestine-specific transcribed regions occurs at the rate of -0.37% per month (P < 0.01, Pearson = -0.57). The dynamic resetting of the DNA methylome in the neobladder not only implicates local environmental cues in the shaping and maintenance of the epigenome but also illustrates an unexpected cross-talk between the epigenome and the cellular environment.

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“…Because enhancer activity has been associated with transcription of enhancer RNAs (eRNAs) (16,(18)(19)(20)(21) we analyzed the density of nuclear long and short RNA on enhancers from RNA-seq experiments in MCF7 cells (Methods). We found that AGO1-bound enhancers have significantly higher density of long nuclear RNAs relative to enhancers without significant AGO1 signal (P < 0.005) (Fig.…”

Section: Ago1 Preferentially Associates With Active Enhancers But Doementioning

confidence: 99%

Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells

Alló

Agirre

Bessonov

et al. 2014

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

103

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The roles of Argonaute proteins in cytoplasmic microRNA and RNAi pathways are well established. However, their implication in small RNA-mediated transcriptional gene silencing in the mammalian cell nucleus is less understood. We have recently shown that intronic siRNAs cause chromatin modifications that inhibit RNA polymerase II elongation and modulate alternative splicing in an Argonaute-1 (AGO1)-dependent manner. Here we used chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) to investigate the genome-wide distribution of AGO1 nuclear targets. Unexpectedly, we found that about 80% of AGO1 clusters are associated with cell-type-specific transcriptional enhancers, most of them (73%) overlapping active enhancers. This association seems to be mediated by long, rather than short, enhancer RNAs and to be more prominent in intragenic, rather than intergenic, enhancers. Paradoxically, crossing ChIP-seq with RNA-seq data upon AGO1 depletion revealed that enhancer-bound AGO1 is not linked to the global regulation of gene transcription but to the control of constitutive and alternative splicing, which was confirmed by an individual gene analysis explaining how AGO1 controls inclusion levels of the cassette exon 107 in the SYNE2 gene.Argonaute proteins | transcriptional enhancers | alternative splicing A lternative splicing was initially seen as an interesting mechanism to explain protein diversity but affecting a limited number of mammalian genes. The recent development of high-throughput sequencing technologies has dramatically changed this view, generating a renewed interest in alternative splicing. We now know that alternative splicing affects transcripts from more than 90% of human genes (1) and that normal and pathological cell differentiation not only depends on differential gene expression but also on alternative splicing patterns. Mutations in alternative splicing regulatory sequences and factors are involved in the etiology of numerous hereditary diseases, premature aging, and cancer (2).Recently, amid an avalanche of papers reporting various connections between the chromatin context and splicing (3-9), a relationship between splicing and small RNAs has emerged. The convergence of these previously unrelated areas (RNA interference, chromatin, and splicing) has been studied by our laboratory, showing that siRNAs (20-25 nt long) targeting both intronic and exonic regions near the cassette exon 33 (E33, also known as EDI) of the fibronectin gene were able to regulate its alternative splicing by affecting the chromatin context at the target region, with an increase of histone tail modifications associated with gene silencing (H3K9me2 and H3K27me3, i.e., dimethylation of lysine 9 and trimethylation of lysine 27 of histone H3 respectively). Moreover, this effect was shown to be dependent on Argonaute proteins (AGO1 and AGO2) and involves a decrease of RNA polymerase II (RNAPII) elongation, which concomitantly up-regulates E33 inclusion into the mature mRNA (3). More recently, a similar effect was fou...

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Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development

Cited by 465 publications

References 69 publications

Drosophilapoised enhancers are generated during tissue patterning with the help of repression

Drosophilapoised enhancers are generated during tissue patterning with the help of repression

Reprogramming of the human intestinal epigenome by surgical tissue transposition

Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells

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