Why did the DNA methylation cross the road? To cross-talk to the histone methyltransferase on the other side! In the epigenetics, cross-talk is how different marks “talk” to each other during development and is still something of mystery. NSD1 and SETD2 encode enzymes that chemically modify H3K36me2 and H3K36me3 respectively. Germline mutations in these genes cause Sotos and Sotos-like syndrome, (associated with DNA methylation changes) and somatic mutations are associated with numerous cancers. A related disorder is seen in patients with variants in the de novo DNA methyltransferase DNMT3A, consistent with H3K36me being known to influence the activity of DNMT3A. DNA methylation deposited by DNMT3A is important in germline development in male and female mouse gametes, but sperm and oocytes appear to be very different.
The lab of Matthew Lorincz (University of British Columbia, Canada), in collaboration with Wei Xie and colleagues at Tsinghua University, recently showed that that SETD2 is required for Dnmt3a-dependent DNA methylation during oogenesis. In a new study, the Lorincz lab wanted to investigate whether SETD2 had the same role in male germ cells and why sperm have such higher levels of DNA methylation. Using various mouse knockouts, they characterized changes occurring in oocytes and spermatozoa using ultra-low-input native ChIP-seq (ULI-N-ChIP-seq), low-input WGBS using the post-bisulfite adaptor tagging (PBAT) method with the terminal deoxyribonucleotidyl transferase–assisted adenylate connector–mediated single-stranded-DNA ligation technique, and RNA-seq. Here’s what they found:
- In prenatal prospermatogonia of a conditional knockout (cKO) of Setd2, H3K36me3 is greatly reduced, but DNA methylation is unaffected, indicating SETD2 is not required for DNA methylation in spermatogonia as it is in oocytes
- H3K36me2 is highly concordant with de novo DNA methylation in prenatal prospermatogonia, suggesting a role of for a different H3K36me methyltransferase
- In Nsd1 cKO mice, there is dramatically lower (>20% reduction) DNA methylation across a third of the genome in prenatal prospermatogonia
- cKO mice display a loss of spermatogonial stem cells, hypogonadism, and infertility, demonstrating that Nsd1 is necessary for spermatogenesis
- Genes essential for the expansion of prospermatogonia are downregulated and show increased levels of H3K27me3, suggesting aberrant polycomb group-mediated silencing following the loss of H3K36me2
- This ultimately suggests that Nsd1 safeguards a subset of genes from transcriptional repression
Senior author Matthew Lorincz concludes, “Taken together, these observations reveal that male and female germ cells employ distinct H3K36 methyltransferases to direct DNA methylation across the genome. These findings shed light on the cross-talk between essential epigenetic marks and on the etiology of developmental disorders and cancers in which these genes are mutated.”
Catch all the epigenetic cross-talk in Nature Genetics, September 2020