Targeted H3R26 deimination specifically facilitates estrogen receptor binding by modifying nucleosome structure.

Michael J Guertin,Xuesen Zhang,Scott A Coonrod,Lynne Anguish,Gordon L Hager,Sohyoung Kim,Lyuba Varticovski,John T Lis,Jason Carroll

doi:10.1371/journal.pgen.1004613

Michael J Guertin, Xuesen Zhang + Show 7 more

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https://doi.org/10.1371/journal.pgen.1004613

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Abstract

Transcription factor binding to DNA in vivo causes the recruitment of chromatin modifiers that can cause changes in chromatin structure, including the modification of histone tails. We previously showed that estrogen receptor (ER) target gene activation is facilitated by peptidylarginine deiminase 2 (PAD2)-catalyzed histone H3R26 deimination (H3R26Cit). Here we report that the genomic distributions of ER and H3R26Cit in breast cancer cells are strikingly coincident, linearly correlated, and observed as early as 2 minutes following estradiol treatment. The H3R26Cit profile is unlike that of previously described histone modifications and is characterized by sharp, narrow peaks. Paired-end MNase ChIP-seq indicates that the charge-neutral H3R26Cit modification facilitates ER binding to DNA by altering the fine structure of the nucleosome. Clinically, we find that PAD2 and H3R26Cit levels correlate with ER expression in breast tumors and that high PAD2 expression is associated with increased survival in ER+ breast cancer patients. These findings provide insight into how transcription factors gain access to nucleosomal DNA and implicate PAD2 as a novel therapeutic target for ER+ breast cancer.

Highlights

The nucleosome represents the fundamental unit of chromatin and consists of 147 bp of DNA wrapped,1.7 times around the histone octamer core particle [1]
While estrogen receptor (ER) interacts with nucleosome remodelers to maintain the accessible chromatin state [7,8,9], we find that concomitant increases in accessibility at ER binding sites are less prevalent than with other nuclear receptors
ER and H3R26Cit are highly concordant We previously demonstrated that peptidylarginine deiminase 2 (PAD2) binds to chromatin and regulates gene expression in MCF-7 cells via histone deimination

Summary

Introduction

The nucleosome represents the fundamental unit of chromatin and consists of 147 bp of DNA wrapped ,1.7 times around the histone octamer core particle [1]. The N-terminal tails of histones are disordered and reside outside of core nucleosome/DNA structure but they harbor amino acid residues that can be posttranslationally modified to regulate many facets of transcription These modifications can influence transcription factor access to nucleosomal DNA by modulating electrostatic interactions between histones and DNA. We found that PAD2mediated deimination of histone H3 arginine 26 (H3R26Cit) is important for estradiol (E2)-mediated activation of ER-target genes [12] We examine this E2-induced deamination at high temporal and spatial resolution and test the hypothesis that PAD2 facilitates ER/DNA binding by neutralizing the H3R26 charge of local nucleosomes via deimination, thereby weakening histone tail-DNA interactions and destabilizing DNA interactions with the core nucleosome particle

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Discussion

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