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Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions

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Listed:
  • Pawel Nowialis

    (University of Florida College of Medicine
    University of Florida)

  • Katarina Lopusna

    (University of Florida College of Medicine
    University of Florida)

  • Jana Opavska

    (University of Florida College of Medicine
    University of Florida)

  • Staci L. Haney

    (University of Nebraska Medical Center)

  • Ajay Abraham

    (University of Florida College of Medicine
    University of Florida)

  • Peike Sheng

    (University of Florida College of Medicine)

  • Alberto Riva

    (University of Florida)

  • Amarnath Natarajan

    (986805 Nebraska Medical Center)

  • Olga Guryanova

    (University of Florida College of Medicine)

  • Melanie Simpson

    (NC State University)

  • Ryan Hlady

    (Mayo Clinic)

  • Mingyi Xie

    (University of Florida
    University of Florida College of Medicine)

  • Rene Opavsky

    (University of Florida College of Medicine
    University of Florida)

Abstract

DNA methylation regulates gene expression in a variety of processes, including mouse embryonic development. Four catalytically active enzymes function in mice as DNA methyltransferases (Dnmts) and as transcriptional regulators. Inactivation of Dnmt3b results in mouse embryonic lethality, but which activities are involved is unclear. Here we show that catalytically inactive Dnmt3b restores a majority of methylation and expression changes deregulated in the absence of Dnmt3b, and as a result, mice survive embryonic development. Thus, Dnmt3b functions as an accessory cofactor supporting catalytic activities performed by other Dnmts. We further demonstrate that Dnmt3b is linked to a control of major developmental pathways, including Wnt and hedgehog signaling. Dnmt3b directly represses Wnt9b whose aberrant up-regulation contributes to embryonic lethality of Dnmt3b knockout embryos. Our results highlight that Dnmt3b is a multifaceted protein that serves as an enzyme, an accessory factor for other methyltransferases, and as a transcriptional repressor in mouse embryogenesis.

Suggested Citation

  • Pawel Nowialis & Katarina Lopusna & Jana Opavska & Staci L. Haney & Ajay Abraham & Peike Sheng & Alberto Riva & Amarnath Natarajan & Olga Guryanova & Melanie Simpson & Ryan Hlady & Mingyi Xie & Rene O, 2019. "Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12355-7
    DOI: 10.1038/s41467-019-12355-7
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    Cited by:

    1. Simon Andrews & Christel Krueger & Maravillas Mellado-Lopez & Myriam Hemberger & Wendy Dean & Vicente Perez-Garcia & Courtney W. Hanna, 2023. "Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Clara Cousu & Eléonore Mulot & Annie Smet & Sara Formichetti & Damiana Lecoeuche & Jianke Ren & Kathrin Muegge & Matthieu Boulard & Jean-Claude Weill & Claude-Agnès Reynaud & Sébastien Storck, 2023. "Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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