Abstract

DNA methylation is a chemical modification that occurs predominantly on CG dinucleotides in mammalian genomes. However, recent studies from our laboratory have revealed that non-CG methylation (mCH) is more abundant than CG methylation and non-randomly distributed in the genomes of brain cells. mCH accumulates during the establishment of neural circuits and is associated with Rett syndrome. A comprehensive understanding of how neural circuits spanning the entire brain generate the full repertoire of perception and behaviors requires a list of brain cell types, as well the means to target each cell type in order to interrogate the functional interactions that give rise to the emergent properties of the whole system. Neuronal diversity is essential for mammalian brain function but poses a challenge to molecular profiling. To facilitate cell-type-specific epigenomic studies, we have developed approaches to isolate nuclei from subtypes of neocortical neurons, revealing highly distinctive epigenomic landscapes. Hundreds of thousands of regions differ in chromatin accessibility and DNA methylation signatures characteristic of gene regulatory regions which are predicted to bind distinct cohorts of neuron subtype-specific transcription factors. Surprisingly, neuronal epigenomes reflect both past and present gene expression, with DNA hyper-methylation at developmentally critical genes appearing as a novel epigenomic signature in mature neurons. More recently, we have developed single cell methylome profiling methods that now allow an unbiased census of the diversity of neuronal cell types in the mammalian brain. We are using these approaches to begin to link the functional and transcriptional complexity of neurons throughout the brain to their underlying epigenomic diversity.