Wilson Lab - EMBO Reports Authors Taglini. F., Kafetzopoulos, I., Rolls, W., Musialik, K.I., Lee, H.Y., Zhang, Y., Marenda, M., Kerr, L., Finan, H., Rubio-Ramon, C., Gautier, P., Wapenaar, H., Kumar, D., Davidson-Smith, H., Wills, J., Murphy, L.C., Wheeler, A., Wilson, M.D., and Sproul, D. Summary of Paper by Eleanor Casey Genetic silencing ensures that the right genes are expressed, in the right place, at the right time, and is essential for humans to develop normally and to prevent cancer. Silencing is in part achieved by DNA methylation. The mammalian genome relies heavily on methylation as a means to silence genes, particularly in transcriptionally inactive regions of the genome known as heterochromatin. The DNA methyl transferase DNMT3B is one of the proteins that puts methylation on DNA and is found mutated in a number of conditions. In this paper the Wilson lab (WCB) and Sproul lab (Institute Genetics and Cancer) joined forces aiming to understand how DNMT3B is recruited to the genome, and to determine the effect of DNMT3B mutations on methylation patterns. In cells lacking DNMT3B the authors discovered a surprising loss of methylation at H3K9me3 nucleosomes which mark heterochromatin, rather than the expected gene bodies. To unpick the mechanism for DNMT3B recruitment to H3K9me3 marked heterochromatin, the authors delete different DNMT3B domains and observe how this affects DNA methylation in H3K9me3 heterochromatin. Deletions or mutations of the PWWP chromatin binding domain resulted in increased methylation of H3K9me3 heterochromatin, while deletions of the N terminal domain of DNMT3B resulted in decreased methylation of H3K9me3. The N terminal domain of DNMT3B goes to heterochromatin by bridging with heterochromatin protein 1 alpha (HP1a), a highly conserved protein which is crucial to establish and maintain heterochromatin. The interaction between HP1a and DNMT3B greatly increased its affinity for H3K9me3. The authors conclude that DNMT3B therefore plays an important role in DNA methylation homeostasis at heterochromatin, unexpectedly using its N-terminal region. Image Model outlining the two conflicting recruitment mechanisms of dnmt3b to gene bodies and heterochromatin, mediated by interaction with a heterochromatin protein HP1 Related Links Journal URL Wilson Lab Website DOI This article was published on 2024-06-17
