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

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 and Rene Opavsky ()
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Pawel Nowialis: University of Florida College of Medicine
Katarina Lopusna: University of Florida College of Medicine
Jana Opavska: University of Florida College of Medicine
Staci L. Haney: University of Nebraska Medical Center
Ajay Abraham: University of Florida College of Medicine
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
Rene Opavsky: University of Florida College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12355-7

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