H3S28 phosphorylation is a hallmark of the transcriptional response to cellular stress.

Anna Sawicka,Karl Mechtler,Dominik Hartl,Oliver Pusch,Malgorzata Goiser,Roman R Stocsits,Ido M Tamir,Christian Seiser

doi:10.1101/gr.176255.114

Abstract

The selectivity of transcriptional responses to extracellular cues is reflected by the deposition of stimulus-specific chromatin marks. Although histone H3 phosphorylation is a target of numerous signaling pathways, its role in transcriptional regulation remains poorly understood. Here, for the first time, we report a genome-wide analysis of H3S28 phosphorylation in a mammalian system in the context of stress signaling. We found that this mark targets as many as 50% of all stress-induced genes, underlining its importance in signal-induced transcription. By combining ChIP-seq, RNA-seq, and mass spectrometry we identified the factors involved in the biological interpretation of this histone modification. We found that MSK1/2-mediated phosphorylation of H3S28 at stress-responsive promoters contributes to the dissociation of HDAC corepressor complexes and thereby to enhanced local histone acetylation and subsequent transcriptional activation of stress-induced genes. Our data reveal a novel function of the H3S28ph mark in the activation of mammalian genes in response to MAP kinase pathway activation.

Highlights

Inducible transcription programs converge on the activation of sequence-specific transcription factors that recruit histone-modifying enzymes, which enables the deposition of stimulus-specific chromatin modifications at signal-responsive gene regulatory elements (Smith and Shilatifard 2010; Johnson and Dent 2013)
In these cells, triggering of the p38 MAP kinase pathway with the stress inducer anisomycin enabled us to study the phosphorylation of H3S28 in the absence of excessive mitotic histone H3 phosphorylation found at condensed chromosomes (Spite et al 2007)
The H3S28ph mark was enriched at promoters and 59 untranslated regions (UTRs) (Fig. 1A), with 53% of H3S28ph-marked regions overlapping with CpG islands

Summary

Introduction

Inducible transcription programs converge on the activation of sequence-specific transcription factors that recruit histone-modifying enzymes, which enables the deposition of stimulus-specific chromatin modifications at signal-responsive gene regulatory elements (Smith and Shilatifard 2010; Johnson and Dent 2013). One example of such a signal-inducible chromatin mark that couples signal transduction to gene regulation is the phosphorylation of histone H3. Using a combination of ChIP-seq, RNA-seq, and mass spectrometry approaches, we identified genomic targets of stress-induced H3S28ph and factors involved in the biological interpretation of this histone modification.

Methods

Results

Conclusion