A Unique Histone 3 Lysine 14 Chromatin Signature Underlies Tissue-Specific Gene Regulation

Isabel Regadas,Mattias Mannervik,Sergey Belikov,Sebastian Deindl,Jiayu Wen,Olle Dahlberg,Oanh Ho,Roshan Vaid,Gunjan Dixit

doi:10.2139/ssrn.3720008

Abstract

Organismal development and cell differentiation critically depend on chromatin state transitions. However, certain developmentally regulated genes lack histone 3 lysine 9 and 27 acetylation (H3K9ac and H3K27ac) and H3K4 methylation, histone modifications common to most active genes. Here, we describe a chromatin state featuring unique H3K14ac peaks in key tissue-specific genes in Drosophila and human cells. Replacing H3K14 with arginine in Drosophila demonstrates that H3K14 is essential for expression of genes devoid of canonical histone modifications in the embryonic gut and larval wing imaginal disc, causing lethality and defects in wing patterning. We find that the bromodomain in the SWI/SNF protein Brahma (Brm) recognizes H3K14ac, that brm acts in the same genetic pathway as H3K14R, and that chromatin accessibility at H3K14ac-unique genes is decreased in H3K14R mutants. Our results show that acetylation of a single lysine is essential at genes devoid of canonical histone marks and uncover an important requirement for H3K14 in tissue-specific gene regulation.

Highlights

Cellular differentiation and the response to environmental cues require altered gene expression and are associated with changes in chromatin state (Allis and Jenuwein, 2016; Atlasi and Stunnenberg, 2017)
A unique H3K14ac chromatin state The presence of H3K14ac in promoter regions is positively correlated with active gene expression in yeast and in mammalian cells (Karmodiya et al, 2012; Pokholok et al, 2005), suggesting an important biological role of H3K14ac in transcription activation
In stark contrast to these reports and to other histone modifications associated with active transcription, 30% of H3K14ac is found in exons in Drosophila

Summary

Introduction

Cellular differentiation and the response to environmental cues require altered gene expression and are associated with changes in chromatin state (Allis and Jenuwein, 2016; Atlasi and Stunnenberg, 2017). Histone 3 lysine 27 trimethylation (H3K27me3) is found at Polycomb group (PcG)-repressed genes, whereas histone 3 lysine 4 trimethylation (H3K4me3) is often present at the promoters of transcriptionally active genes (Black et al, 2012). Some developmental genes lack these canonical histone marks but are transcriptionally active (Perez-Lluch et al, 2015). Whether these developmental genes bear another histone mark or whether they are completely devoid of histone modifications altogether is not known. We investigate the role of histone 3 lysine 14 acetylation (H3K14ac) in developmental gene expression and find that a group of tissue-specific genes that lack canonical histone marks are decorated uniquely with this histone modification

Results

Discussion

Conclusion