The mammalian brain is a highly complex organ that integrates diverse sensory inputs, allowing us to adapt to changes in our environment. The intricate architecture of the brain mimics its diverse functionality and is composed of numerous neuronal and glial subtypes. How this diversity in form and function arises in cells with the same genome is thought to be coordinated by specific programs of gene expression. It is becoming increasingly clear that dysregulation of these transcriptional programs during development and in adulthood has a profoundly detrimental impact on brain health. The induction of cell-type-specific gene networks in peripheral cells is controlled by the bromodomain and extraterminal domain-containing (BET) protein family 1; however their function in the central nervous system is largely unknown. My dissertation identifies fundamental roles for BET proteins in the developing and adult brain. We show that BETs are epigenetic regulators of neuronal and synaptic genes involved in ASD-like behaviors in mice. Second, we describe the transcriptional control of microglial inflammation by BETs, highlighting the diverse cell type-specific functions of these proteins. Lastly we show that, in mature neurons, BETs promote metabolic gene network expression and inhibition of this network increases neuronal lifespan and survival in response to toxic stimuli. This work provides a comprehensive examination of the role of BET-dependent transcription in the central nervous system and offers a novel strategy for the treatment of neurodegenerative disorders.
|Commitee:||Benson, Deanna, Nestler, Eric, Casaccia, Patrizia, Akbarian, Schahram, Bateup, Helen|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 81/9(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology|
|Keywords:||Regulation of transcription|
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