SRA

The adult brain is composed of hundreds of different neuronal subtypes, which retain their differentiated traits and identity throughout the lifespan of the organism. Nevertheless, in part due to technical limitations, the mechanisms governing this stability are not fully understood. Here, using a strategy that allows for ChIP-seq combined with RNA-seq in sparse neuronal populations in vivo, we present, to our knowledge, the first comparative analysis of permissive and repressive histone modifications in adult midbrain dopaminergic neurons, raphe nuclei serotonergic neurons and embryonic neural progenitors. Our results support a model wherein a sequential deposition of the repressive modifications H3K27me3 and H3K9me3 occur on developmental genes in a neuronal subtype specific manner. We furthermore show that aberrant gene expression during dopaminergic stress in a mouse model of Parkinson's disease, or after methamphetamine injection, is characterized by the de-repression of genes with promoter regions that are dually marked by H3K4me3 and H3K27me3, whereas the induction of genes with promoter regions marked by any other combination of H3K27me3 and H3K9me3 occur less frequently. Our study provides to our knowledge the first genome-wide analysis of permissive/repressive histone modifications coupled to gene expression in these rare but clinically relevant neuronal subtypes. This strategy can be generalized for the identification and functional characterization of molecular determinants involved in the maintenance of gene expression in other classes of neurons. Overall design: 10 samples of 1000 neuronal nuclei were analyzed in total, 4 samples of adult mDA nuclei, 3 samples of adult SER nuclei and 3 samples of E11.5 Sox2 positive NPC nuclei. Each sample originate from individual mice. Nuclei from these samples were also used for ChIP-seq.