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, Rene Opavsky

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Article number4374
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Nowialis, P., Lopusna, K., Opavska, J., Haney, S. L., Abraham, A., Sheng, P., Riva, A., Natarajan, A., Guryanova, O., Simpson, M., Hlady, R., Xie, M., & Opavsky, R. (2019). Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions. Nature communications, 10(1), [4374]. https://doi.org/10.1038/s41467-019-12355-7