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

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.

Genome-wide investigation of the dynamic changes of epigenome modifications after global DNA methylation editing

“…Similarly, expression of different DNMT3A variants with mutations in the PWWP domain, which abrogate chromatin targeting caused preferential methylation at H3K27me3 containing regions, suggesting that they are most prone to de novo methylation ( 67 , 68 ). Recently, the positive correlation of DNA methylation and H3K27me3 has also been reported in a genetic study in mice expressing a catalytically inactive DNMT3B enzyme ( 69 ). A similar effect was also observed after ectopic expression of untargeted DNMT3B ( 51 ).…”

Dnmt3b catalytic activity is critical for its tumour suppressor function in lymphomagenesis and is associated with c-Met oncogenic signalling

“…Mice harbouring conventional knock-in mutations (P656V and C657D) in Dnmt3b coding sequence (Dnmt3bCI) were generated as described before [13] . PCR-based genotyping was carried out as previously [13] . EμSRα-tTA;Teto-MYC mice were obtained from D.W. Felsher (Stanford University).…”

“…Only early passages were used. Mouse MYC-induced T-cell lymphoma line was established as described before [ 13 , 21 ]. Cells were maintained in DMEM or RPMI 1640 (Invitrogen) containing 10% foetal bovine serum.…”

“…through association with HDACs [9] , [10] , [11] . Dnmt3L and Dnmt3b also possess accessory function (AF) that consist of the ability to recruit other Dnmts to genomic loci to catalyse methylation [ 8 , 12 , 13 ].…”

Metabolism as a central regulator of β‐cell chromatin state

“…It also occurs in the gene bodies of highly transcribed genes and can recruit complexes that enhance transcription [73]. DNMT3a and DNMT3b are responsible for de novo DNA methylation during cell development [74][75][76] whereas DNMT1 is involved in maintenance of methylation throughout DNA replication [77][78][79]. Methylated sites interfere with transcription factor binding and recruit methyl-binding proteins that facilitate heterochromatin formation [80].…”