Project 445428

Our proposal focuses on understanding Kabuki syndrome, a genetic condition characterized by specific facial features, intellectual disability and growth deficiency. Kabuki syndrome occurs due to a change (mutation) in a gene that functions as an epigenetic regulator. Epigenetic regulators control the activity of other genes by adding or removing chemical marks and informing each cell about which genes need to be turned on or turned off. The pattern and timing of epigenetic mark placement are critical for healthy development. To date, there are ~70 genetic conditions caused by mutations in different epigenetic regulators characterized by intellectual disability. We have found that for each condition, a unique pattern of epigenetic marks can be identified that furthers our understanding of the disorder. This grant outlines a plan to better understand the genetic and epigenetic changes that lead to Kabuki syndrome as a starting point for studying the broader group of conditions caused by deficiencies in epigenetic regulators. We will study the pattern of epigenetic marks in human blood and neural cells (generated from blood) from individuals with Kabuki syndrome. We will compare these marks in different types of cells to understand how they lead to the characteristic features of Kabuki syndrome. We will also compare a Kabuki mouse model to control mice to identify changes in epigenetic marks between blood and brain tissues. Then we will investigate if epigenetic changes due to Kabuki syndrome can be reversed in mice that show improved memory and learning following drug treatment. If we find that epigenetic marks are normalized in response to drug treatments that improve brain function, this could speed up the process of identifying drugs for human clinical trials. We anticipate that findings from this study will be of tremendous value in advancing our understanding of Kabuki syndrome, its molecular causes, and potential treatments.