This week we profile a recent publication in Nature Genetics from Dr. Kenjiro Shirane (pictured, back) in
the laboratory of Dr. Matthew Lorincz (pictured, sixth from right) at the UBC Life Sciences Institute.
Can you provide a brief overview of your lab’s current research focus?
Research in the lab is directed towards understanding the interplay between DNA methylation and covalent histone modifications in transcriptional regulation, with a focus on the germline and early embryonic development. Using the mouse as a model system, we employ CRISPR/Cas9 and conventional genetic knockouts of chromatin factors combined with genome-wide analyses of chromatin states to dissect the roles of specific epigenetic marks in the regulation of developmental genes and repetitive elements. These studies are made possible by methods developed or optimized in the lab for genome-wide analyses from small numbers of cells, using in house pipelines developed to integrate the analyses of epigenomic and transcriptomic datasets. Elucidating the crosstalk between specific epigenetic marks and their influence on gene expression will hopefully yield fundamental insights into the molecular basis of both developmental disorders and cancers in which the chromatin modifying enzymes that deposit these marks are mutated.
What is the significance of the findings in this publication?
Reprogramming of the epigenome is a hallmark of cellular differentiation in mammals, in particular during gametogenesis and early in embryonic development. While a striking difference in the levels and distribution of DNA methylation in mature oocytes and sperm of mice was recognized a number of years ago, the molecular basis of this difference has remained a mystery. Furthermore, how the essential but distinct genomic imprints established in prospermatogonia (the cells that give rise to sperm) and oocytes remained unclear. In this publication, we show that “de novo” DNA methylation, including at imprinted genes, is directed in the genome of prospermatogonia by a specific modification on the amino-terminus of histone H3, namely lysine 36 (H3K36). This mark is deposited by the histone methyltransferase NSD1 and mice lacking the Nsd1 gene are sterile. Surprisingly, de novo DNA methylation in oocytes is not dependent on NSD1. Rather, as we showed previously (Nature Genetics 2019), de novo DNA methylation in the female germline is dependent upon the related H3K36 histone methyltransferase SETD2, which marks the bodies of active genes. Unlike NSD1, SETD2 is dispensable for DNA methylation in prospermatogonia. Taken together, these observations reveal that the sexually dimorphic pattern of DNA methylation and specific genes imprinted in the mouse can be explained at least in part by the distinct histone H3K36 methyltransferases that are expressed in these cells. Intriguingly, NSD1 is mutated in the overgrowth disorder Sotos Syndrome, as well as in multiple cancers, including head and neck squamous cell carcinoma. Cells from patients with these diseases also show reduced levels of DNA methylation, indicating that NSD1 may generally play a critical role in the establishment of this epigenetic mark, and in turn in regulating normal patterns of cellular differentiation.
What are the next steps for this research?
We are currently using NSD1 and SETD2 conditional knock out lines to study the roles that these histone methyltransferases play in early embryonic development, in particular on the epigenome and the regulation of genes essential for germ lineage commitment.
This work was funded by:
CIHR.
