Grant: Project Grant

Human overgrowth disorders such as Sotos syndrome are characterized by pre- and postnatal increased growth, intellectual disability and facial anomalies. These diseases result from mutations in genes that encode enzymes that turn off other genes by changing the structure of DNA. These genes include NSD1, most frequently mutated in Sotos Syndrome patients, and SETD2. Both encoded enzymes chemically modify a specific amino acid on a specific protein associated with DNA called histone H3. Other patients with overgrowth syndromes have mutations in the gene Dnmt3a, which encodes an enzyme that chemically modifies the DNA itself. Interestingly, the modifications of histone H3 influences the activity of the protein that modifies the DNA, as well as that of another protein, EZH2, which chemically modifies histone H3.The ezh2 gene is mutated in the related overgrowth disorder called Weaver Syndrome. These observations suggest "cross-talk" between these enzymes and in turn the genes they regulate. However, a systematic study of the consequences of disrupting these regulatory proteins has not been conducted. Here, using the mouse as a model system, we will study the interplay between these enzymes and the marks they deposit, by mutating these "overgrowth syndrome genes" in the mouse and studying the consequences of such mutations in the early mouse embryo, where these genes are first active. This "genome-wide" study, using state-of-the-art sequencing technology and mouse genetics, will lead to a better understanding of the molecular basis of several human overgrowth syndromes including Sotos and Weaver, potentially leading to new avenues for treatment of these diseases.