NEUTIME · The role of nuclear architectural RNAs in the long-term maintenance of the neural epigenome

Neurons in the brain must function for a life-time with limited replacement; thus, they need to robustly maintain their identity and function. Understanding the mechanisms underlying the longevity and persistence of neurons will be key for preventing and treating age-related neurological diseases. By focusing on epigenetic mechanisms regulated by nuclear RNAs, the project aims at understanding the fundamental mechanisms underlying the long-term maintenance of neural identity and their biological roles in the development of age-related vulnerability. The successful completion of this proposal will uncover novel roles of RNAs in long-term epigenetic regulation, and key biological links between epigenetic dysregulation and age-related pathological development.We recently discovered that some nuclear RNAs in rodent brains do not turn over for two years. These RNAs are maintained in a neural cell type-specific manner and are mainly localized around heterochromatin. Through a targeted approach, satellite RNA was found to be one of the stable nuclear RNAs and is critical for the maintenance of heterochromatin. Based on this finding, the proposed project aims to test the specific hypothesis that neural cells possess several long-retained nuclear RNAs which interact with chromatin to stabilize cell type-specific epigenetic regulation, but that they deteriorate as a result of aging. To address this question, we will use an interdisciplinary approach. First, the molecular identity of long-retained nuclear RNAs will be probed globally using deep sequencing. In parallel, mechanisms responsible for maintaining RNAs will be investigated Second, the roles of the nuclear RNAs and associated complexes we identify in maintaining cell type-specific epigenetic regulation will be investigated using neurobiological, epigenomic and biochemical approaches. Efforts will be directed toward understanding the roles of nuclear RNAs in pathophysiological brain aging.