Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.

TitleHistone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.
Publication TypeJournal Article
Year of Publication2022
AuthorsGuo P, Liu Y, Geng F, Daman AW, Liu X, Zhong L, Ravishankar A, Lis R, DurĂ¡n JGabriel Ba, Itkin T, Tang F, Zhang T, Xiang J, Shido K, Ding B-sen, Wen D, Josefowicz SZ, Rafii S
JournalNat Cell Biol
Volume24
Issue1
Pagination99-111
Date Published2022 Jan
ISSN1476-4679
KeywordsAnimals, CD8-Positive T-Lymphocytes, Cell Cycle Proteins, Cell Line, Chromatin, Granulocytes, Hematopoiesis, Hematopoietic Stem Cells, Histone Chaperones, Histones, Human Umbilical Vein Endothelial Cells, Humans, Macrophages, Methylation, Mice, Mice, Inbred C57BL, Mice, Knockout, Myelopoiesis, Promoter Regions, Genetic, Protein Processing, Post-Translational, Transcription Factors
Abstract

Histone variants and the associated post-translational modifications that govern the stemness of haematopoietic stem cells (HSCs) and differentiation thereof into progenitors (HSPCs) have not been well defined. H3.3 is a replication-independent H3 histone variant in mammalian systems that is enriched at both H3K4me3- and H3K27me3-marked bivalent genes as well as H3K9me3-marked endogenous retroviral repeats. Here we show that H3.3, but not its chaperone Hira, prevents premature HSC exhaustion and differentiation into granulocyte-macrophage progenitors. H3.3-null HSPCs display reduced expression of stemness and lineage-specific genes with a predominant gain of H3K27me3 marks at their promoter regions. Concomitantly, loss of H3.3 leads to a reduction of H3K9me3 marks at endogenous retroviral repeats, opening up binding sites for the interferon regulatory factor family of transcription factors, allowing the survival of rare, persisting H3.3-null HSCs. We propose a model whereby H3.3 maintains adult HSC stemness by safeguarding the delicate interplay between H3K27me3 and H3K9me3 marks, enforcing chromatin adaptability.

DOI10.1038/s41556-021-00795-7
Alternate JournalNat Cell Biol
PubMed ID34961794
PubMed Central IDPMC9166935
Grant ListR01 GM129380 / GM / NIGMS NIH HHS / United States
R35 HL150809 / HL / NHLBI NIH HHS / United States
T32 GM007273 / GM / NIGMS NIH HHS / United States
RC2 DK114777 / DK / NIDDK NIH HHS / United States
RM1 GM139738 / GM / NIGMS NIH HHS / United States
U01 AI138329 / AI / NIAID NIH HHS / United States
R01 AI148416 / AI / NIAID NIH HHS / United States
R01 HL130826 / HL / NHLBI NIH HHS / United States
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