Grant: Project Grant

In the human body, every cell consists of the same DNA genetic material. Yet, the same copy of DNA is capable of making all the different cell types found in the body, e.g. a skin cell, a muscle cell, or a neuron. This process of cell differentiation is caused by a specific combination of genes being turned on/off at a specific moment in time. This regulation of the genetic material is called "epi-genetics" (epi- "above"), and it involves modifications of histones, the DNA packaging protein, by enzymes such as SETD2. In humans, alterations of SETD2 can lead to birth defects of the brain, resulting in either larger or smaller than normal size brains. SETD2 patients also exhibit intellectual disability and autistic-like behavioral deficits. Our research program aims to understand the role of SETD2 in the development of the normal brain and how mutations in this gene can lead to disease. We will use mouse models to study SETD2 deficiency in detail by examining epigenetic features and gene expression capacity. We will also create "brain in a petri dish" cerebral organoid models in the lab to simulate the effects of SETD2 mutation in the nervous system. By doing this, we hope to uncover important genes that interact with these epigenetic mutations, and elucidate the molecular mechanism of neurodevelopmental diseases.