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
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引用次数: 0
摘要
缺氧通过抑制氧和α-酮戊二酸依赖的去甲基化酶来增强组蛋白甲基化，导致组蛋白甲基化增加。这项研究揭示了缺氧诱导的甲基化如何影响IMR90人成纤维细胞在癌基因诱导的衰老（OIS）过程中组蛋白剪切和异染色质重组为衰老相关的异染色质灶（SAHF）。值得注意的是，通过自上而下的蛋白质组学，我们发现了在Raf激活过程中H3、H2B和H4中被Cathepsin L （CTSL）靶向的特定切割位点，确定了H2B和H4中的新位点。缺氧通过促进甲基化而不影响CTSL活性来抵消CTSL介导的组蛋白剪切。正如ATAC-seq分析所显示的那样，缺氧下甲基化的增加可以防止剪切，重塑表观遗传景观并影响染色质可及性。这些见解强调了缺氧诱导的组蛋白甲基化在细胞衰老过程中保护染色质免受显着表观遗传变化的关键作用。
Hypoxia increases methylated histones to prevent histone clipping and heterochromatin redistribution during Raf-induced senescence.
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.
期刊介绍：
Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.
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