It’s not always easy to find good friends, but recent work has found that the de novo DNA methyltransferases DNMT3A2 and DNMT3B1 are far from socially awkward.
Baubec et al. from the Swiss team lead by Dirk Schübeler uncovered some companions of these DNMTs by profiling their binding in embryonic stem cells (ESCs) through streptavidin ChIP-sequencing of biotin tagged functional proteins.
This experiment led to some interesting findings including the observation that binding occurred at CpG rich region and not at H3K4me3 regions. In addition:
- DNMT3B1 could bind mainly at gene bodies where it made friends such as PolII and H3K36me3, a mark of active transcription, deposited by SETD2.
- When DNMT3B1 and DNMT3A2 were reintroduced in methylation deficient cells (triple knockouts of DNMTs) they could rescue an astonishing total of 1% (out of 4% total) of DNA methylation, with DNMT3A2 more processive than B1.
- Mapping of these reintroduced DNMTs revealed that DNMT3A2 methylates closely to a seeding CpG dinucleotide that could be orchestrated by nucleosomes.
- DNA methylation occurred primarily at nucleosomes linker regions.
- Strikingly, even the reintroduced DNMT3B1 was observed at gene bodies mirroring highly transcribed genes, but especially at sites of H3K36me3.
- Confirming this dependency, when the authors differentiated the ESCs, in which DNMT3B is expressed, into neuronal progenitors, H3K36me3 relocates and consequently so does its friend DNMT3B1.
- RNA pol II elongation inhibition does not affect H3K36me3 binding and DNMT3B1 positioning.
- The friendship could only be broken by CRISPR/Cas9 deletion of SETD2, which impairs the recruitment of DNMT3B1 to active genes, or by mutations in the PWWP domain of DNMT3B1 observed in ICF syndrome patients that mediate the binding to H3K36me3.
These finding show a role for DNMT3B in genic methylation and help to shed light on how de novo methylation is guided by a relationship with H3K36me3.
Further details about this exciting friendship can be found in Nature, January 2015.