Histone H3K4me1 strongly activates the DNase I hypersensitive sites in super-enhancers than those in typical enhancers.

Jin Kang,Yujin Kang,Aeri Kim

doi:10.1042/bsr20210691

Abstract

Super-enhancers (SEs), which consist of multiple enhancer elements, are occupied by master transcription factors and co-activators, such as Mediator, and are highly acetylated at histone H3K27. Here, we have characterized the SEs in terms of DNase I hypersensitive sites (DHSs) by analyzing publicly available chromatin immunoprecipitation (ChIP)-seq and DNase-seq data of K562 cells and compared with the DHSs in typical enhancers (TEs). DHSs in the SEs were highly marked by histone H3K4me1 than DHSs in TEs. Loss of H3K4me1 by the deletion of catalytic domains in histone methyltransferases MLL3 and MLL4 remarkably decreased histone H3K27ac and histone H3 depletion at SE DHSs than at TE DHSs. The levels of enhancer RNA (eRNA) transcripts and mRNA transcripts from the putative target genes were notably reduced at and near SE DHSs than TE DHSs following H3K4me1 loss. These results indicate that histone H3K4me1 is a marker for DHSs in SEs and that this modification has a more significant impact on the activation of SE DHSs than TE DHSs.

Highlights

Enhancers are cis-regulatory elements that regulate cell type-specific gene expression [1,2]
We identified our enhancer elements by overlapping the DNase-seq peaks and histone H3K27ac chromatin immunoprecipitation (ChIP)-seq peaks in erythroid K562 cells and by excluding CTCF binding sites using NGS data obtained from the Encyclopedia of DNA Elements (ENCODE) curated by UCSC (Figure 1A, left)
These enhancer elements that were identified as DNase I hypersensitive site (DHS) have a more active chromatin structure in SEs than typical enhancers (TEs)

Summary

Introduction

Enhancers are cis-regulatory elements that regulate cell type-specific gene expression [1,2]. They are often classified into super-enhancers (SEs) and typical enhancers (TEs) depending on their enrichment of Mediator or histone H3K27ac and the clustering of other enhancer elements within 12.5 kb [3,4,5]. Loss of H3K4me by the mutation or depletion of histone methyltransferases MLL3 (KMT2C) and MLL4 (KMT2D) negatively affects H3K27ac at enhancers and results in transcriptional inhibition of target genes in mammalian cells [12,13,14]. Enhancer RNAs (eRNAs) are transcribed in an H3K4me1-dependent manner [12,16]. These findings provide insight into the fundamental roles of H3K4me in activating enhancers

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Results

Conclusion