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

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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 (US)
Pages (from-to)	1721-1735
Number of pages	15
Journal	Nature genetics
Volume	54
Issue number	11
DOIs	https://doi.org/10.1038/s41588-022-01212-x
State	Published - Nov 2022

ASJC Scopus subject areas

Genetics

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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, YH, 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, no. 11, pp. 1721-1735. https://doi.org/10.1038/s41588-022-01212-x

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

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.",

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 Tsai, {Yi Hsuan} 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 = "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",

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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

PY - 2022/11

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N2 - 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.

AB - 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.

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Histone H3 proline 16 hydroxylation regulates mammalian gene expression

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