Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence

Soojeong Chang; Ramhee Moon; Dowoon Nam; Sang Won Lee; Insoo Yoon; Dong Sung Lee; Seunghyuk Choi; Eunok Paek; Daehee Hwang; Junho K. Hur; Youhyun Nam; Rakwoo Chang; Hyunsung Park

doi:10.1093/nar/gkae1210

Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence

Soojeong Chang
, Ramhee Moon
, Dowoon Nam
, Sang Won Lee
, Insoo Yoon
, Dong Sung Lee
, Seunghyuk Choi
, Eunok Paek
, Daehee Hwang
, Junho K. Hur
, Youhyun Nam
, Rakwoo Chang
, Hyunsung Park

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Hypoxia enhances histone methylation by inhibiting oxygen- and α-ketoglutarate-dependent demethylases, resulting in increased methylated histones. This study reveals how hypoxia-induced methylation affects histone clipping and the reorganization of heterochromatin into senescence-associated heterochromatin foci (SAHF) during oncogene-induced senescence (OIS) in IMR90 human fibroblasts. Notably, using top-down proteomics, we discovered specific cleavage sites targeted by Cathepsin L (CTSL) in H3, H2B and H4 during Raf activation, identifying novel sites in H2B and H4. Hypoxia counteracts CTSL-mediated histone clipping by promoting methylation without affecting CTSL’s activity. This increase in methylation under hypoxia protects against clipping, reshaping the epigenetic landscape and influencing chromatin accessibility, as shown by ATAC-seq analysis. These insights underscore the pivotal role of hypoxia-induced histone methylation in protecting chromatin from significant epigenetic shifts during cellular aging.

Original language	English
Article number	gkae1210
Journal	Nucleic Acids Research
Volume	53
Issue number	3
DOIs	https://doi.org/10.1093/nar/gkae1210
State	Published - 10 Feb 2025

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title = "Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence",

abstract = "Hypoxia enhances histone methylation by inhibiting oxygen- and α-ketoglutarate-dependent demethylases, resulting in increased methylated histones. This study reveals how hypoxia-induced methylation affects histone clipping and the reorganization of heterochromatin into senescence-associated heterochromatin foci (SAHF) during oncogene-induced senescence (OIS) in IMR90 human fibroblasts. Notably, using top-down proteomics, we discovered specific cleavage sites targeted by Cathepsin L (CTSL) in H3, H2B and H4 during Raf activation, identifying novel sites in H2B and H4. Hypoxia counteracts CTSL-mediated histone clipping by promoting methylation without affecting CTSL{\textquoteright}s activity. This increase in methylation under hypoxia protects against clipping, reshaping the epigenetic landscape and influencing chromatin accessibility, as shown by ATAC-seq analysis. These insights underscore the pivotal role of hypoxia-induced histone methylation in protecting chromatin from significant epigenetic shifts during cellular aging.",

author = "Soojeong Chang and Ramhee Moon and Dowoon Nam and Lee, \{Sang Won\} and Insoo Yoon and Lee, \{Dong Sung\} and Seunghyuk Choi and Eunok Paek and Daehee Hwang and Hur, \{Junho K.\} and Youhyun Nam and Rakwoo Chang and Hyunsung Park",

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doi = "10.1093/nar/gkae1210",

language = "English",

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T1 - Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence

AU - Chang, Soojeong

AU - Moon, Ramhee

AU - Nam, Dowoon

AU - Lee, Sang Won

AU - Yoon, Insoo

AU - Lee, Dong Sung

AU - Choi, Seunghyuk

AU - Paek, Eunok

AU - Hwang, Daehee

AU - Hur, Junho K.

AU - Nam, Youhyun

AU - Chang, Rakwoo

AU - Park, Hyunsung

PY - 2025/2/10

Y1 - 2025/2/10

N2 - Hypoxia enhances histone methylation by inhibiting oxygen- and α-ketoglutarate-dependent demethylases, resulting in increased methylated histones. This study reveals how hypoxia-induced methylation affects histone clipping and the reorganization of heterochromatin into senescence-associated heterochromatin foci (SAHF) during oncogene-induced senescence (OIS) in IMR90 human fibroblasts. Notably, using top-down proteomics, we discovered specific cleavage sites targeted by Cathepsin L (CTSL) in H3, H2B and H4 during Raf activation, identifying novel sites in H2B and H4. Hypoxia counteracts CTSL-mediated histone clipping by promoting methylation without affecting CTSL’s activity. This increase in methylation under hypoxia protects against clipping, reshaping the epigenetic landscape and influencing chromatin accessibility, as shown by ATAC-seq analysis. These insights underscore the pivotal role of hypoxia-induced histone methylation in protecting chromatin from significant epigenetic shifts during cellular aging.

AB - Hypoxia enhances histone methylation by inhibiting oxygen- and α-ketoglutarate-dependent demethylases, resulting in increased methylated histones. This study reveals how hypoxia-induced methylation affects histone clipping and the reorganization of heterochromatin into senescence-associated heterochromatin foci (SAHF) during oncogene-induced senescence (OIS) in IMR90 human fibroblasts. Notably, using top-down proteomics, we discovered specific cleavage sites targeted by Cathepsin L (CTSL) in H3, H2B and H4 during Raf activation, identifying novel sites in H2B and H4. Hypoxia counteracts CTSL-mediated histone clipping by promoting methylation without affecting CTSL’s activity. This increase in methylation under hypoxia protects against clipping, reshaping the epigenetic landscape and influencing chromatin accessibility, as shown by ATAC-seq analysis. These insights underscore the pivotal role of hypoxia-induced histone methylation in protecting chromatin from significant epigenetic shifts during cellular aging.

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DO - 10.1093/nar/gkae1210

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JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 3

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ER -

Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence

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