Gene expression during early development of primordial germ cells (PGCs) is sex-specific.
Research led by Professor Petra Hajkova from the Reprogramming and Chromatin research group at the Medical Research Council London Institute of Medical Sciences has shown for the first time that germ cells, which give rise to either sperm or egg cells, have different epigenetic pathways to regulate gene expression.
'Epigenetic reprogramming is a highly orchestrated progress during the germline life cycle,' said Dr Tien-Chi Huang, a post-doc and first author of the paper published in Nature. He added: 'Our study provides a long-awaited answer to understand how germ cells coordinate different layers of controls to maintain gene expression during this process.'
During early development of PGCs in mammals, widespread DNA demethylation occurs. DNA methylation is an epigenetic mechanism used to regulate the transcription of genes. When a methyl group is added to DNA, gene expression is silenced. When DNA is demethylated, uncontrolled transcription can occur. Despite the widespread demethylation observed in PGCs, uncontrolled gene expression does not occur. This suggests the presence of other epigenetic mechanisms that regulate gene expression.
The researchers aimed to identify the mechanisms that regulate gene expression after DNA demethylation occurs in early development. They observed that methylation of K27 on histone-3 (H3K27me3) compensates for DNA demethylation in both female and male germ cells. This system was found to be critical for female germ cells, however, male germ cells were also able to use methylation of K9 on histone-3 (H3K9me3) to regulate gene expression.
The researchers then used a mouse model to delete Ezh2, the gene responsible for K27 methylation. This had a profound effect on female germ cells – loss of H3K27me3 resulted in uncontrollable gene expression, resulting in cell death. However, male germ cells were not affected. While this mechanism is critical for female germ cells to differentiate into egg cells, male germ cells can use other mechanisms to differentiate into sperm cells – methylation of K9 on histone-3.
'These results teach us something fundamental about the control of gene expression,' said Professor Hajkova. '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 has frequently been observed in cancer. An improved understanding into epigenetic silencing systems will allow the development of new therapeutic agents, with EZH2 and DNA enzymes already identified as targets.