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The histone H2A deubiquitinase Usp16 regulates embryonic stem cell gene expression and lineage commitment

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  • Wei Yang

    (Stem Cell Institute, University of Alabama at Birmingham)

  • Yun-Hwa Lee

    (Yong Loo Lin School of Medicine, National University of Singapore)

  • Amanda E. Jones

    (Stem Cell Institute, University of Alabama at Birmingham)

  • Jessica L. Woolnough

    (Stem Cell Institute, University of Alabama at Birmingham)

  • Dewang Zhou

    (Stem Cell Institute, University of Alabama at Birmingham)

  • Qian Dai

    (University of Alabama at Birmingham, West Pavilion)

  • Qiang Wu

    (Yong Loo Lin School of Medicine, National University of Singapore)

  • Keith E. Giles

    (Stem Cell Institute, University of Alabama at Birmingham)

  • Tim M. Townes

    (Stem Cell Institute, University of Alabama at Birmingham)

  • Hengbin Wang

    (Stem Cell Institute, University of Alabama at Birmingham)

Abstract

Polycomb Repressive Complex 1 and histone H2A ubiquitination (ubH2A) contribute to embryonic stem cell (ESC) pluripotency by repressing lineage-specific gene expression. However, whether active deubiquitination co-regulates ubH2A levels in ESCs and during differentiation is not known. Here we report that Usp16, a histone H2A deubiquitinase, regulates H2A deubiquitination and gene expression in ESCs, and importantly, is required for ESC differentiation. Usp16 knockout is embryonic lethal in mice, but does not affect ESC viability or identity. Usp16 binds to the promoter regions of a large number of genes in ESCs, and Usp16 binding is inversely correlated with ubH2A levels, and positively correlates with gene expression levels. Intriguingly, Usp16−/− ESCs fail to differentiate due to ubH2A-mediated repression of lineage-specific genes. Finally, Usp16, but not a catalytically inactive mutant, rescues the differentiation defects of Usp16−/− ESCs. Therefore, this study identifies Usp16 and H2A deubiquitination as critical regulators of ESC gene expression and differentiation.

Suggested Citation

  • Wei Yang & Yun-Hwa Lee & Amanda E. Jones & Jessica L. Woolnough & Dewang Zhou & Qian Dai & Qiang Wu & Keith E. Giles & Tim M. Townes & Hengbin Wang, 2014. "The histone H2A deubiquitinase Usp16 regulates embryonic stem cell gene expression and lineage commitment," Nature Communications, Nature, vol. 5(1), pages 1-15, September.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4818
    DOI: 10.1038/ncomms4818
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    1. Gaozan Tong & Yiming Chen & Xixi Chen & Junfu Fan & Kunxuan Zhu & ZiJing Hu & Santie Li & Junjie Zhu & Jianjun Feng & Zhaohang Wu & Zhenyu Hu & Bin Zhou & Litai Jin & Hui Chen & Jingling Shen & Weitao, 2023. "FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Julian Cheron & Leonardo Beccari & Perrine Hagué & Romain Icick & Chloé Despontin & Teresa Carusone & Matthieu Defrance & Sagar Bhogaraju & Elena Martin-Garcia & Roberto Capellan & Rafael Maldonado & , 2023. "USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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