Systematic Examination of Epigenomic Regulation of Neuronal Plasticity

Abstract

<p>The epigenome underlies cell type and state and in post-mitotic neurons, and it regulates the ability for rapid response to activity. Since neurons exit the cell cycle early in development and are long lived, remodeling of brain function requires that neurons show transcriptional plasticity to let then change in function in response to stimuli including psychostimulants and developmental cues. This response is driven by the epigenomic regulation in a cell-type-specific manner. Many studies assessing experience driven genomic responses have been carried out in bulk tissues so cell-type-specific genomic responses to stimuli that drive neuronal plasticity remains poorly understood. To understand the epigenomic and transcriptomic mechanisms driving neuronal plasticity, here we study multi-omic genomic data from two contexts in the mouse brain: 1) psychostimulant responses in the nucleus accumbens and 2)the postnatal and postmitotic maturation of developing cerebellar granule neurons. In both systems, I implemented integrative bioinformatic approaches to predict transcription factor (TF) activity in regulating the transcriptome. I elucidated cell-type-specific amphetamine induced transcriptomic responses, identified canonical activity regulated transcription factors regulating those responses, and determined collaborators and developmental targets of the Zic family TFs, revealing novel roles of Zics regulating migration and synaptic maturation in CGN development. The studies reveal novel mechanistic insights into neuronal plasticity in different neuronal cell types by using integrative computational approaches to model chromatin topology, chromatin accessibility, gene expression, and TF binding. </p>