Grant: Project Grant

During development, genes must be activated or silenced at precise times and places in order for an embryo to make all of the right tissues and survive. This is done in part by DNA methylation, which is a chemical modification of DNA critical for "silencing" genes. DNA methylation is also responsible for silencing transposons. These parasitic DNA elements act like viruses, except that they make copies of themselves and multiply within the genome itself. Transposons can cause dangerous mutations within the cell if not kept in check. For an embryo to develop properly, DNA methylation from the previous generation must be removed and replaced. We discovered that a protein called ZMYM2 is important for promoting the DNA methylation of key genes and transposons. Mice lacking ZMYM2 die early in development, expressing the wrong genes and showing explosive activation of transposons. ZMYM2 does not bind DNA or cause DNA methylation by itself, it works with other proteins in order to go to the right parts of the genome and make sure the right genes and transposons get methylated. The goal of our project is to figure out what other proteins ZMYM2 interacts with, and how it interacts with them, in order to silence genes. We also want to find out what ZMYM2 does during the formation of germ cells (future sperm or egg). Germ cells also must reset all of their DNA methylation, so we want to see whether ZMYM2 has the same functions and works with the same proteins. Humans with only one copy of ZMYM2 (instead of the usual two) suffer from a serious genetic disorder and have problems with the kidney, the brain and other systems. This shows that ZMYM2 is likely to be important at many points in human development, and is important for human health. Our project will determine some of the basics of how it acts and what it does.