Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions.
Animals
Biocatalysis
DNA (Cytosine-5-)-Methyltransferases
/ genetics
DNA Methylation
Embryonic Development
/ genetics
Female
Gene Expression Regulation, Developmental
HEK293 Cells
Hedgehog Proteins
/ genetics
Humans
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Signal Transduction
/ genetics
Wnt Proteins
/ genetics
DNA Methyltransferase 3B
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 09 2019
26 09 2019
Historique:
received:
05
04
2019
accepted:
04
09
2019
entrez:
28
9
2019
pubmed:
29
9
2019
medline:
7
1
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31558711
doi: 10.1038/s41467-019-12355-7
pii: 10.1038/s41467-019-12355-7
pmc: PMC6763448
doi:
Substances chimiques
Hedgehog Proteins
0
Wnt Proteins
0
Wnt9b protein, mouse
0
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4374Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM128753
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA178191
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121831
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA190886
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188561
Pays : United States
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