Scientists discover chromatin-modifying enzyme crucial for normal development

Over the past few years, covalent modifications of histone tails have emerged as an important mechanism of gene regulation in eukaryotes. Now, scientists have identified a major euchromatic histone methyltransferase in mammalian cells that is crucial for normal embryonic development, and possibly the prevention of cancer. In a report published in Genes & Development, Dr. Yoichi Shinkai and colleagues have identified a protein called G9a as an enzyme that adds a methyl group to the lysine 9 amino acid residue on the histone H3 proteins that are associated with euchromatic (transcriptionally active) DNA in the mammalian genome. The researchers genetically engineered live mice and murine stem cells to lack G9a in order to determine the function of the protein.

G9a-deficient mice died between embryonic day 9.5 and 12.5, and displayed severe developmental growth retardation. In fact, the G9a-deficient mouse embryos did not appear to develop beyond embryonic day 8.5. The researchers determined that this developmental growth arrest is due, at least in part, to aberrant ly high levels of programmed cell death during embryogenesis.

G9a-deficient stem cells displayed a marked decrease in histone H3 lysine 9 methylation, and were unable to differentiate into embryonic cell types in culture. Taken together, the in vivo and in vitro evidence suggests that G9a-mediated histone H3 lysine 9 methylation serves to regulate the expression of crucial genes during development.

Dr. Shinkai and colleagues found that one of the genes regulated by G9a-mediated methylation is Mage-2a, which encodes a tumor-specific protein whose function is currently unknown. The researchers show that Mage-2a expression is induced in G9a-deficient cells, and, as Dr. Shinkai points out, “This may suggest that deregulation of histone H3 lysine 9 methylation is involved in some type of tumorigenesis.”

Further delineation of other G9a target genes will elucidate the full physiological role of euchromatic G9a-mediated histone H3 lysine 9 methylation, but as this work by Dr. Shinkai and colleagues shows, the role of G9a in development is already proving to be an important one.