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Nucleic Acids Res., Dec 11 2024, gkae1210 | https://doi.org/10.1093/nar/gkae1210
Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence
Soojeong Chang1, Ramhee Moon1, Dowoon Nam2, Sang-Won Lee2, Insoo Yoon1, Dong-Sung Lee1, Seunghyuk Choi3, Eunok Paek3, Daehee Hwang4, Junho K. Hur5, Youhyun Nam6, Rakwoo Chang6 and Hyunsung Park1,6,*
1Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
2Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
3Department of Computer Science, Hanyang University, Seoul 04763, Republic of Korea
4School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
5Department of Genetics, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
6Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea
*To whom correspondence should be addressed.
1Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
2Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
3Department of Computer Science, Hanyang University, Seoul 04763, Republic of Korea
4School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
5Department of Genetics, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
6Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea
*To whom correspondence should be addressed.
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.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2024-12-18)
- 국내 연구진
- 생명과학 > 세포생물학
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