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

Peipei Guo*, Ying Liu, Fuqiang Geng, Andrew W. Daman, Xiaoyu Liu, Liangwen Zhong, Arjun Ravishankar, Raphael Lis, José Gabriel Barcia Durán, Tomer Itkin, Fanying Tang, Tuo Zhang, Jenny Xiang, Koji Shido, Bi sen Ding, Duancheng Wen*, Steven Z. Josefowicz, Shahin Rafii*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)99-111
Number of pages13
JournalNature Cell Biology
Issue number1
StatePublished - Jan 2022
Externally publishedYes


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