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

doi:10.1038/s41556-021-00795-7

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 journal › Article › peer-review

20 Scopus citations

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.

Original language	English
Pages (from-to)	99-111
Number of pages	13
Journal	Nature Cell Biology
Volume	24
Issue number	1
DOIs	https://doi.org/10.1038/s41556-021-00795-7
State	Published - Jan 2022
Externally published	Yes

Funding

Funders	Funder number
Ansary Stem Cell Institute
Empire State Stem Cell Board NYSTEM	C030160
New York State Stem Cell Science Program	R01 GM129380-01, C32581GG
Weill Cornell Medicine, Starr Foundation Stem Cell Core Project	TRI-SCI 2019-029
National Institutes of Health	R35 HL150809, U01AI138329, RC2 DK114777
National Heart, Lung, and Blood Institute	R01HL130826, C34052GG
National Institute of Allergy and Infectious Diseases	R01AI148416

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41556-021-00795-7

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Guo, P., Liu, Y., Geng, F., Daman, A. W., Liu, X., Zhong, L., Ravishankar, A., Lis, R., Barcia Durán, J. G., Itkin, T., Tang, F., Zhang, T., Xiang, J., Shido, K., Ding, B. S., Wen, D., Josefowicz, S. Z., & Rafii, S. (2022). Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability. Nature Cell Biology, 24(1), 99-111. https://doi.org/10.1038/s41556-021-00795-7

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title = "Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability",

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.",

author = "Peipei Guo and Ying Liu and Fuqiang Geng and Daman, {Andrew W.} and Xiaoyu Liu and Liangwen Zhong and Arjun Ravishankar and Raphael Lis and {Barcia Dur{\'a}n}, {Jos{\'e} Gabriel} and Tomer Itkin and Fanying Tang and Tuo Zhang and Jenny Xiang and Koji Shido and Ding, {Bi sen} and Duancheng Wen and Josefowicz, {Steven Z.} and Shahin Rafii",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = jan,

doi = "10.1038/s41556-021-00795-7",

language = "אנגלית",

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Guo, P, Liu, Y, Geng, F, Daman, AW, Liu, X, Zhong, L, Ravishankar, A, Lis, R, Barcia Durán, JG, Itkin, T, Tang, F, Zhang, T, Xiang, J, Shido, K, Ding, BS, Wen, D, Josefowicz, SZ & Rafii, S 2022, 'Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability', Nature Cell Biology, vol. 24, no. 1, pp. 99-111. https://doi.org/10.1038/s41556-021-00795-7

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T1 - Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability

AU - Guo, Peipei

AU - Liu, Ying

AU - Geng, Fuqiang

AU - Daman, Andrew W.

AU - Liu, Xiaoyu

AU - Zhong, Liangwen

AU - Ravishankar, Arjun

AU - Lis, Raphael

AU - Barcia Durán, José Gabriel

AU - Itkin, Tomer

AU - Tang, Fanying

AU - Zhang, Tuo

AU - Xiang, Jenny

AU - Shido, Koji

AU - Ding, Bi sen

AU - Wen, Duancheng

AU - Josefowicz, Steven Z.

AU - Rafii, Shahin

PY - 2022/1

Y1 - 2022/1

N2 - 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.

AB - 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.

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SN - 1465-7392

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EP - 111

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 1

ER -

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

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