biostudies-literatureGuo PNIDDK NIH HHSNIAID NIH HHSNHLBI NIH HHSEuropean Hematology AssociationNIH HHSNIGMS NIH HHS99-111https://www.ebi.ac.uk/biostudies/studies/S-EPMC9166935biostudies-literatureUnknown24(1)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 Nature cell biologyHistone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.PMC9166935RM1 GM139738R35 HL150809R01 AI148416U01 AI138329TRTH153R01 GM129380R01 HL130826R21 OD031973RC2 DK114777Ding BSLis RXiang JTang FGuo PDaman AWLiu XLiu YZhang TRavishankar AGeng FBarcia Duran JGItkin TShido KRafii SWen DZhong LJosefowicz SZfalseHistone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.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 2022-01-01T00:00:00Z2022 Jan2026-06-03T10:18:33.531Z2025-02-18T23:36:08.462ZS-EPMC91669353496179410.1038/s41556-021-00795-7