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Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influences on MEF2-dependent transcription

ABSTRACT: Purpose: Define the chromatin remodelling induced by second generation HDACIs Outcome: We demonstrate that NKL54 treatment increased the number of H3K27ac peaks and caused a slight redistribution of H3K27ac peaks in promotorial regions. The hyperacetylation effect is evident in poorly acetylated loci, while hyperacetylated TSS turned out to be paradoxically deacetylated by NKL54 treatment. NKL54 caused a reduction in the binding of HDAC4 and HDAC9, especially at the intergenic regions. Instead, their binding to promoters was conserved. In contrast, NKL54 caused a dramatic increase in MEF2D binding to several genomic regions and especially to promoters. These new NKL54-enhanced MEF2D-chromatin interactions are often located at new genomic regions, whereas 40% of MEF2D peaks in untreated cells are conserved in NKL54-treated cells. Importantly, in these new regions, MEF2D is frequently recruited in the absence of HDAC4 or of HDAC9.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180681 | GEO | 2022/01/25

REPOSITORIES: GEO

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Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells

Project description:Purpose: Define the transcriptional networks supervising class IIa HDAC expression. Outcome: We demonstrate that MEF2D is the key factor controlling HDAC9 transcription. Comprehensive genome-wide studies demonstrate that HDAC4 and HDAC9 supervise different genetic programs and show both specific and common genomic bindings. Although the number of MEF2-target genes commonly regulated is similar, only HDAC4 represses many additional genes that are not MEF2D targets. HDAC4-/- and HDAC9-/- cells increase H3K27ac levels around the TSS of the respective repressed genes. However, these genes rarely show bindings of the HDACs at their promoters. Frequently HDAC4 and HDAC9 bind intergenic regions. We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers.

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Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells.

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Project description:Abstract. Very little is known regarding how hormonal exposures impact the epigenetic landscape of developing tissues in the context of a whole organism, in contrast to the impact on cultured cells. Here we took a global approach to understanding how neonatal exposure to the xenoestrogen, diethylstilbestrol (DES), alters the uterine epigenome. RNA-seq and ChIP-seq (H3K4me3, H3K27me3, H3K27ac and H3K4me1) were performed on DES-treated and control uteri. The most striking finding was differential association of H3K27ac and H3K4me1 at typical and super-enhancer regions of 79% of altered genes. These peaks overlapped with previously reported estrogen receptor a (ERα) ChIP-seq peaks. Conditional uterine deletion of ERα (Esr1cKO) conferred protection of 88% of altered genes. H3K27ac ChIP-seq on Esr1cKO samples showed that 72% of protected genes had a differential H3K27ac enhancer. These data suggest that DES regulates gene expression in the neonatal mouse uterus by H3K27ac association at ERα binding sites near estrogen-regulated genes.

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ERα Dependent Alterations in the Epigenetic Landscape of the Mouse Uterus Following Neonatal Estrogen Exposure [RNA-Seq]

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