Grant: Project Grant

Each cell in an individual has the same genetic code, yet our body consists of many different cell types. This is a result of our cells intrinsic ability to turn genes on and off, depending on which genes are needed within that specific cell type. Genes are regulated in part by "epigenetic proteins" including histones, the proteins around which the DNA is wrapped, and the chemical marking of these proteins. The presence of the "linker" histone called H1 is known to influence the activity of enzymes that deposit these marks, and in turn the genes they control, by bringing other histones associated with DNA closer together in physical space. Interestingly, mutations within the gene that encodes linker histone H1.4 leads to the neurodevelopmental disorder (NDD) known as Rahman syndrome, while mutations in other genes that encode epigenetic enzymes are responsible for a number of NDDs with similar epigenetic and clinical outcomes, including Sotos and Weaver Syndromes. Disruption of any one of the genes encoding these proteins leads to a cascade of changes, disturbing the balance between epigenetic marks and in turn causing mis-regulation of other genes and eventually the relevant NDD. Understanding how these epigenetic enzymes and histone H1.4 work together to regulate other genes is crucial for understanding how mutations in H1.4 cause disease. We propose to study the impact of the Rahman Syndrome H1.4 mutations by: 1. identifying the proteins that interact with mutant versus normal H1 (using an approach called "TurboID"), and 2. using state-of-the-art genetic engineering to generate a cell culture system in which the mutant form of H1.4 seen in disease is produced and in turn we can study the epigenetic alterations occurring in neuronal cells in Rahman syndrome. We anticipate that this work will generate important molecular insights into the epigenetic pathways disrupted in Rahman Syndrome that will aid in the development of new treatments for this and related NDDs.