Researchers from the MRC London Institute of Medical Sciences (LMS) have uncovered how primordial germ cells (PGCs) regulate their gene expression in the absence of DNA methylation, and have shown for the first time that this gene repression is sex-specific.

Although our DNA contains in excess of 20,000 genes, only a subset of those genes are active in each individual cell. Which gene will be activated is a highly regulated process, and one epigenetic mechanism (a mechanism that doesn’t change the DNA sequence) that regulates this process is DNA methylation. Cells use DNA methylation to silence gene expression, essentially ‘turning off’ a gene.

During mammalian embryonic development, PGCs (primordial germ cells, the embryonic precursors of gametes) undergo the process of “epigenetic reprogramming”, which involves the removal of almost all DNA methylation, before differentiating into either egg or sperm. This has left scientists questioning how PGCs regulate their gene expression, and what mechanisms they use to silence genes that should not be active.

Researchers from the LMS Reprogramming and Chromatin research group revealed that instead of using DNA methylation, PGCs use alternative repressive epigenetic systems and these systems are employed differently in male and female germ cells. Using an ultra-low input native chromatin immunoprecipitation (ULI-nChIP) approach, the team found that methylation of K27 on histone-3 (H3K27me3) compensates for the loss of DNA methylation in PGCs. Female germ cells critically rely on this system whereas the male germ cells also utilise methylation of K9 on histone-3 (H3K9me3).

To explore this further in a physiological setting, the group used a mouse model where the gene required for H3K27me3 methylation, Ezh2, had been removed. The removal of this key gene led to the uncontrollable expression of genes and of transposable elements in female germ cells, ultimately leading to cell death. However, this was not the case in the male germ cells. They were unaffected by the knockout of Ezh2 as they were able to use methylation of K9 on histone-3 as an alternative back-up.

Dr Tien-Chi Huang, post-doc in Professor Hajkova’s group and first author of the paper said: “Epigenetic reprogramming is a highly orchestrated progress during the germline life cycle. Our study provides a long-awaited answer to understand how germ cells coordinate different layers of controls to maintain gene expression during this process.”

Professor Petra Hajkova, Head of the LMS Reprogramming and Chromatin Research Group said: “These results teach us something fundamental about the control of gene expression. What we have seen looking into the development of embryonic germline has a much broader impact because we know that a number of human pathologies are characterised by global reduction of DNA methylation. This means our results provide valuable insights into what the diseased cells need to rely on to control their genes, revealing their potential vulnerabilities.”

Loss of DNA methylation, also known as DNA hypomethylation, has been frequently observed in cancer. Interestingly, Ezh2 and DNA methyltransferases have been identified as therapeutic targets. Understanding of the mechanistic crosstalk between DNA methylation and the polycomb epigenetic repressive system could open up avenues for the  development of new stratified treatments.

‘Sex-specific chromatin remodelling safeguards transcription in germ cells’ was published in Nature 8 December 2021.