PXD033971-1

PXD033971 is an original dataset announced via ProteomeXchange.

Title	Hypoxia increases the methylated histones to prevent histone clipping and redistribution of heterochromatin during Raf-induced senescence.
Description	Hypoxia in stem cell niches and inner core of solid tumors contributes to cellular senescence and differentiation inhibition. It directly increases histone methylationby inhibiting the activities of O2-and α-ketoglutarate (α-KG)-dependent histone lysine demethylases. This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). This study showed that Raf activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated cleavage of H3, H2B, and H4. Hypoxia prevented H3 cleavage not by inhibiting CTSL but by increasing H3K18me3 and H3K23me3 nearby cleaved site of H3. Forced expression of cleaved H3 in IMR90 cells induced senescence even under hypoxia, suggesting that hypoxia breaks this positive feedback senescence driving circle by increasing methylated histones. The decrease in methylated histones is necessary for OIS to trigger histone clipping and SAHFs, but hypoxia maintains methylated histones to prevent both. Forced reduction of methylated histones in hypoxic cells using inhibitors of methyl-transferases makes hypoxic conditions unable to prevent OIS from inducing both histone clipping and SAHFs. Reversely forced enhancement of methylated histones in normoxic cells using inhibitors of histone demethylases protected histones from clipping during OIS but failed to block SAHFs. Altogether, the maintenance of methylated histones, especially H3K23me3 and H3K18me3, is sufficient to protect histones from clipping during OIS, but not for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other methods to inhibit SAHFs. These findings provide a novel mechanism by which hypoxia affects cell fate by increasing methylated histones that protect histones and chromatin from dramatic epigenetic changes.
HostingRepository	PRIDE
AnnounceDate	2024-11-27
AnnouncementXML	Submission_2024-11-27_10:02:32.059.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dowoon Nam
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monomethylated residue; acetylated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-18 07:30:49	ID requested
⏵ 1	2024-11-27 10:02:32	announced

Dataset with its publication pending

submitter keyword: Human, Top-down, Histone, Proteomics

Sang-Won Lee
contact affiliation	Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
contact email	sw_lee@korea.ac.kr
lab head
Dowoon Nam
contact affiliation	Korea University
contact email	dowoon0517@korea.ac.kr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD033971
     1. Label: PRIDE project
     2. Name: Hypoxia increases the methylated histones to prevent histone clipping and redistribution of heterochromatin during Raf-induced senescence.