Neuron-specific analysis of histone modifications with post-mortem brains

Histone modifications govern chromatin structures and regulate gene expression to orchestrate cellular functions in the central nervous system, where neuronal cells are postmitotic and developmentally inactive, the functional and age-dependent changes also accumulate in the epigenetic states. Because the brain is composed of several types of cells, such as the neurons, glial cells, and vascular cells, the analysis of histone modifications using bulk brain tissue might obscure alterations specific to neuronal cells. Furthermore, among the various epigenetic traits, analysis of the genome-wide distribution of DNA methylation in the bulk brain is predominantly a reflection of DNA methylation of the non-neuronal cells, which may be a potential caveat of previous studies on neurodegenerative diseases using bulk brains. In this study, we established a method of neuron-specific ChIP-seq assay, which allows for the analysis of genome-wide distribution of histone modifications specifically in the neuronal cells derived from post-mortem brains. We successfully enriched neuronal information with high reproducibility and high signal-to-noise ratio. Our method will further facilitate the understanding of neurodegeneration.