Boots, check! Helmet, check! DNA Methylation, check? Any active individual will tell you that protecting your body is an integral part of keeping fit and healthy while enjoying your sport of choice. In the über-competitive world of DNA, a study from the teams of Francesco Neri and Salvatore Oliviero has proposed that DNA methylation on gene “bodies”, i.e. their introns and exons, acts as a protective strategy to keep our cells fit and healthy! In this case, this protection inhibits unwanted intragenic transcription from highly active genes and the possible production of aberrant and potentially dangerous proteins.
Neri et al. employed mouse embryonic stem cells (mESCs) that lacked expression (KO) of the Dnmt3b DNA methyltransferase, as studies suggest that this enzyme establishes de novo DNA methylation after binding to the H3K36me3 histone modification present on gene bodies. Encouragingly, this KO strategy decreased gene body DNA methylation; so what were the consequences?
- Loss of gene body DNA methylation increased levels of cryptic intragenic transcription from highly expressed genes
- The cryptic transcription involved RNA polymerase II (RNAP II) complexes binding to intragenic regions downstream from canonical promoters
- However, DNA methylation loss did not mediate global activation of alternative promoters, also regulated by DNA methylation
- Re-expression of enzymatically active Dnmt3b reduced intragenic transcription initiation in KO mESCs
- This reduction also required the presence of the H3K36me3 modification (via the enzymatic capabilities of SetD2) for gene body recruitment purposes
- The RNA exosome complex degraded a fraction of the cryptic RNAs, although some transcripts became polyadenylated, stabilized, and exported from the nucleus for possible transcription
- mRNA ribosome profiling suggested that decreased gene body DNA methylation and consequent transcription of cryptic RNAs can generate aberrant proteins
Overall, the Dnmt3b-SetD2 axis appears to represent an important protective strategy to keep our cells fit and healthy, especially given the links between tumorigenesis and hypomethylation on intragenic regions, the presence of abnormal RNA transcripts, and mutations in SETD2.
To read more about how cells keep fit and healthy through DNA methylation, see the original study at Nature, Feb 2017.