Dataset Information

Transcription factor-dependent 'anti-repressive' mammalian enhancers exclude H3K27me3 from extended genomic domains.

ABSTRACT: Compacted chromatin and nucleosomes are known barriers to gene expression; the nature and relative importance of other transcriptional constraints remain unclear, especially at distant enhancers. Polycomb repressor complex 2 (PRC2) places the histone mark H3K27me3 predominantly at promoters, where its silencing activity is well documented. In adult tissues, enhancers lack H3K27me3, and it is unknown whether intergenic H3K27me3 deposits affect nearby genes. In primary intestinal villus cells, we identified hundreds of tissue-restricted enhancers that require the transcription factor (TF) CDX2 to prevent the incursion of H3K27me3 from adjoining areas of elevated basal marking into large well-demarcated genome domains. Similarly, GATA1-dependent enhancers exclude H3K27me3 from extended regions in erythroid blood cells. Excess intergenic H3K27me3 in both TF-deficient tissues is associated with extreme mRNA deficits, which are significantly rescued in intestinal cells lacking PRC2. Explaining these observations, enhancers show TF-dependent binding of the H3K27 demethylase KDM6A. Thus, in diverse cell types, certain genome regions far from promoters accumulate H3K27me3, and optimal gene expression depends on enhancers clearing this repressive mark. These findings reveal new "anti-repressive" function for hundreds of tissue-specific enhancers.

SUBMITTER: Saxena M

PROVIDER: S-EPMC5795785 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Transcription factor-dependent 'anti-repressive' mammalian enhancers exclude H3K27me3 from extended genomic domains.

Saxena Madhurima M Roman Adrianna K San AKS O'Neill Nicholas K NK Sulahian Rita R Jadhav Unmesh U Shivdasani Ramesh A RA

Genes & development 20171201 23-24

Compacted chromatin and nucleosomes are known barriers to gene expression; the nature and relative importance of other transcriptional constraints remain unclear, especially at distant enhancers. Polycomb repressor complex 2 (PRC2) places the histone mark H3K27me3 predominantly at promoters, where its silencing activity is well documented. In adult tissues, enhancers lack H3K27me3, and it is unknown whether intergenic H3K27me3 deposits affect nearby genes. In primary intestinal villus cells, we ...[more]

PMID: 29321178

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Project description:BackgroundHistone modifications play a critical role in chromatin remodelling and regulate gene expression in health and disease. Histone methyltransferases EZH1, EZH2, and demethylases UTX, JMJD3, and UTY catalyse trimethylation of lysine 27 on histone H3 (H3K27me3). This study was designed to investigate whether H3K27me3 triggers hyperglycemia-induced oxidative and inflammatory transcriptional programs in the endothelium.MethodsWe studied human aortic endothelial cells exposed to high glucose (HAEC) or isolated from individuals with diabetes (D-HAEC). RT-qPCR, immunoblotting, chromatin immunoprecipitation (ChIP-qPCR), and confocal microscopy were performed to investigate the role of H3K27me3. We determined superoxide anion (O2-) production by ESR spectroscopy, NF-κB binding activity, and monocyte adhesion. Silencing/overexpression and pharmacological inhibition of chromatin modifying enzymes were used to modulate H3K27me3 levels. Furthermore, isometric tension studies and immunohistochemistry were performed in aorta from wild-type and db/db mice.ResultsIncubation of HAEC to high glucose showed that upregulation of EZH2 coupled to reduced demethylase UTX and JMJD3 was responsible for the increased H3K27me3. ChIP-qPCR revealed that repressive H3K27me3 binding to superoxide dismutase and transcription factor JunD promoters is involved in glucose-induced O2- generation. Indeed, loss of JunD transcriptional inhibition favours NOX4 expression. Furthermore, H3K27me3-driven oxidative stress increased NF-κB p65 activity and downstream inflammatory genes. Interestingly, EZH2 inhibitor GSK126 rescued these endothelial derangements by reducing H3K27me3. We also found that H3K27me3 epigenetic signature alters transcriptional programs in D-HAEC and aortas from db/db mice.ConclusionsEZH2-mediated H3K27me3 represents a key epigenetic driver of hyperglycemia-induced endothelial dysfunction. Targeting EZH2 may attenuate oxidative stress and inflammation and, hence, prevent vascular disease in diabetes.

Dataset Information

Transcription factor-dependent 'anti-repressive' mammalian enhancers exclude H3K27me3 from extended genomic domains.

Publications

Transcription factor-dependent 'anti-repressive' mammalian enhancers exclude H3K27me3 from extended genomic domains.

Similar Datasets

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