Histone H3 proline 16 hydroxylation regulates mammalian gene expression

Xijuan Liu, Jun Wang, Joshua A. Boyer, Weida Gong, Shuai Zhao, Ling Xie, Qiong Wu, Cheng Zhang, Kanishk Jain, Yiran Guo, Javier Rodriguez, Mingjie Li, Hidetaka Uryu, Chengheng Liao, Lianxin Hu, Jin Zhou, Xiaobing Shi, Yi-hsuan Tsai, Qin Yan, Weibo LuoXian Chen, Brian D. Strahl, Alex Von Kriegsheim, Qi Zhang, Gang Greg Wang, Albert S. Baldwin, Qing Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Histone post-translational modifications (PTMs) are important for
regulating various DNA-templated processes. Here, we report the
existence of a histone PTM in mammalian cells, namely histone H3 with
hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the
proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding
of KDM5A to its substrate, histone H3 with trimethylation at the fourth
lysine residue (H3K4me3), resulting in enhanced chromatin recruitment
of KDM5A and a corresponding decrease of H3K4me3 at target genes.
Genome- and transcriptome-wide analyses show that the EGLN2–KDM5A
axis regulates target gene expression in mammalian cells. Specifically, our
data demonstrate repression of the WNT pathway negative regulator DKK1
through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/β-catenin
signaling in triple-negative breast cancer (TNBC). This study characterizes
a regulatory mark in the histone code and reveals a role for H3P16oh in
regulating mammalian gene expression
Original languageEnglish
Pages (from-to)1721-1735
JournalNature Genetics
Volume54
Early online date8 Nov 2022
DOIs
Publication statusPublished - Nov 2022

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