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 Luo; Xian Chen; Brian D. Strahl; Alex Von Kriegsheim; Qi Zhang; Gang Greg Wang; Albert S. Baldwin; Qing Zhang

doi:10.1038/s41588-022-01212-x

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 journal › Article › peer-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 language	English
Pages (from-to)	1721-1735
Journal	Nature Genetics
Volume	54
Early online date	8 Nov 2022
DOIs	https://doi.org/10.1038/s41588-022-01212-x
Publication status	Published - Nov 2022

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@article{1c67e467c14c4702b6dd834922381526,

title = "Histone H3 proline 16 hydroxylation regulates mammalian gene expression",

abstract = "Histone post-translational modifications (PTMs) are important forregulating various DNA-templated processes. Here, we report theexistence of a histone PTM in mammalian cells, namely histone H3 withhydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by theproline hydroxylase EGLN2. We show that H3P16oh enhances direct bindingof KDM5A to its substrate, histone H3 with trimethylation at the fourthlysine residue (H3K4me3), resulting in enhanced chromatin recruitmentof KDM5A and a corresponding decrease of H3K4me3 at target genes.Genome- and transcriptome-wide analyses show that the EGLN2–KDM5Aaxis regulates target gene expression in mammalian cells. Specifically, ourdata demonstrate repression of the WNT pathway negative regulator DKK1through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/β-cateninsignaling in triple-negative breast cancer (TNBC). This study characterizesa regulatory mark in the histone code and reveals a role for H3P16oh inregulating mammalian gene expression",

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

note = "Funding Information: We thank all members of the Qing Zhang, A.S.B. and G.G.W. laboratories for helpful discussions and suggestions. This work was supported in part by the National Cancer Institute (R01CA211732 and R01CA256833 to Qing Zhang), Cancer Prevention and Research Institute of Texas (RR190058 to Qing Zhang), American Cancer Society (RSG-18-059-01-TBE to Qing Zhang) and US Department of Defense (W81XWH1910813 to Qing Zhang). A.S.B. is supported by NCI 1R35CA197684, B.D.S. is supported by 1R35GM126900 and G.G.W. is supported by R01CA215284 and R01CA211336. . Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = nov,

doi = "10.1038/s41588-022-01212-x",

language = "English",

volume = "54",

pages = "1721--1735",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Liu, X, Wang, J, Boyer, JA, Gong, W, Zhao, S, Xie, L, Wu, Q, Zhang, C, Jain, K, Guo, Y, Rodriguez, J, Li, M, Uryu, H, Liao, C, Hu, L, Zhou, J, Shi, X, Tsai, Y, Yan, Q, Luo, W, Chen, X, Strahl, BD, Von Kriegsheim, A, Zhang, Q, Wang, GG, Baldwin, AS & Zhang, Q 2022, 'Histone H3 proline 16 hydroxylation regulates mammalian gene expression', Nature Genetics, vol. 54, pp. 1721-1735. https://doi.org/10.1038/s41588-022-01212-x

TY - JOUR

T1 - Histone H3 proline 16 hydroxylation regulates mammalian gene expression

AU - Liu, Xijuan

AU - Wang, Jun

AU - Boyer, Joshua A.

AU - Gong, Weida

AU - Zhao, Shuai

AU - Xie, Ling

AU - Wu, Qiong

AU - Zhang, Cheng

AU - Jain, Kanishk

AU - Guo, Yiran

AU - Rodriguez, Javier

AU - Li, Mingjie

AU - Uryu, Hidetaka

AU - Liao, Chengheng

AU - Hu, Lianxin

AU - Zhou, Jin

AU - Shi, Xiaobing

AU - Tsai, Yi-hsuan

AU - Yan, Qin

AU - Luo, Weibo

AU - Chen, Xian

AU - Strahl, Brian D.

AU - Von Kriegsheim, Alex

AU - Zhang, Qi

AU - Wang, Gang Greg

AU - Baldwin, Albert S.

AU - Zhang, Qing

N1 - Funding Information: We thank all members of the Qing Zhang, A.S.B. and G.G.W. laboratories for helpful discussions and suggestions. This work was supported in part by the National Cancer Institute (R01CA211732 and R01CA256833 to Qing Zhang), Cancer Prevention and Research Institute of Texas (RR190058 to Qing Zhang), American Cancer Society (RSG-18-059-01-TBE to Qing Zhang) and US Department of Defense (W81XWH1910813 to Qing Zhang). A.S.B. is supported by NCI 1R35CA197684, B.D.S. is supported by 1R35GM126900 and G.G.W. is supported by R01CA215284 and R01CA211336. . Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/11

Y1 - 2022/11

N2 - Histone post-translational modifications (PTMs) are important forregulating various DNA-templated processes. Here, we report theexistence of a histone PTM in mammalian cells, namely histone H3 withhydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by theproline hydroxylase EGLN2. We show that H3P16oh enhances direct bindingof KDM5A to its substrate, histone H3 with trimethylation at the fourthlysine residue (H3K4me3), resulting in enhanced chromatin recruitmentof KDM5A and a corresponding decrease of H3K4me3 at target genes.Genome- and transcriptome-wide analyses show that the EGLN2–KDM5Aaxis regulates target gene expression in mammalian cells. Specifically, ourdata demonstrate repression of the WNT pathway negative regulator DKK1through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/β-cateninsignaling in triple-negative breast cancer (TNBC). This study characterizesa regulatory mark in the histone code and reveals a role for H3P16oh inregulating mammalian gene expression

AB - Histone post-translational modifications (PTMs) are important forregulating various DNA-templated processes. Here, we report theexistence of a histone PTM in mammalian cells, namely histone H3 withhydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by theproline hydroxylase EGLN2. We show that H3P16oh enhances direct bindingof KDM5A to its substrate, histone H3 with trimethylation at the fourthlysine residue (H3K4me3), resulting in enhanced chromatin recruitmentof KDM5A and a corresponding decrease of H3K4me3 at target genes.Genome- and transcriptome-wide analyses show that the EGLN2–KDM5Aaxis regulates target gene expression in mammalian cells. Specifically, ourdata demonstrate repression of the WNT pathway negative regulator DKK1through the EGLN2-H3P16oh-KDM5A pathway to promote WNT/β-cateninsignaling in triple-negative breast cancer (TNBC). This study characterizesa regulatory mark in the histone code and reveals a role for H3P16oh inregulating mammalian gene expression

U2 - 10.1038/s41588-022-01212-x

DO - 10.1038/s41588-022-01212-x

M3 - Article

VL - 54

SP - 1721

EP - 1735

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

Histone H3 proline 16 hydroxylation regulates mammalian gene expression

Abstract

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