Grant: Project Grant

Microglia are the immune cells residing in the brain and play key roles in its development maintenance of proper functioning, and immune response against infections and injuries. To date, most pathological conditions affecting the brain, ranging from neurodevelopment disorders like schizophrenia to neurodegenerative diseases like multiple sclerosis, involve an accompanying inflammatory response that is driven by microglia. However, the mechanisms involved in triggering this microglial-driven inflammatory response, or in sustaining it, are not well understood to this day. To large extent, the cellular functions of microglia stem from the genes that these cells express. Work by us and others recently demonstrated that discrete regions of the genome called enhancers are critical to ensure that genes are correctly expressed in microglia. However, how enhancers, in the number of 40,000 in microglia, are regulated in the brain under both under healthy and pathological conditions remains largely unknown. To investigate how these genomic regions contribute to gene regulation, we will characterize the interactions between proteins involved in gene regulation and enhancers. To do so, we will isolate microglia from the mouse brain and perform assays with next-generation sequencing technologies to reveal how enhancers are involved in specifying microglia gene expression in a given context. Collectively, this research program will enable a much greater understanding of the signalling and epigenetic mechanisms that are responsible for gene regulation microglia, and by extension, the mechanisms that underlie the cellular functions of microglia. Thus, precisely defining the epigenetic mechanisms that regulate microglia gene expression in mice as proposed by this research program represents a critical step towards the development of more efficient therapies to treat neuropsychiatric disorders and neurodegenerative diseases.