Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes

Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 2; pp. E142 - E151
Main Authors Zhao, Jingyao, Chen, Xufeng, Song, Guangrong, Zhang, Jiali, Liu, Haifeng, Liu, Xiaolong
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 10.01.2017
SeriesFrom the Cover
Subjects
Biological Sciences
Cell division
DNA methylation
Epigenetics
Gene expression
PNAS Plus
Stem cells
cell-division mode
HSCs
Uhrf1
cell fate decision
epigenetic regulation
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Summary:Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.
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1J. Zhao and X.C. contributed equally to this work.
Edited by Ioannis Aifantis, New York University School of Medicine, New York, NY, and accepted by Editorial Board Member Tak W. Mak November 18, 2016 (received for review August 4, 2016)
Author contributions: J. Zhao, X.C., and X.L. designed research; J. Zhao, X.C., G.S., J. Zhang, and H.L. performed research; J. Zhao, X.C., G.S., J. Zhang, and X.L. analyzed data; and J.Zhao, X.C., and X.L. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1612967114