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Abstract
The brain is composed of hundreds of different neuronal subtypes, which largely retain their identity throughout the lifespan of the organism. The mechanisms governing this stability are not fully understood, partly due to the diversity and limited size of clinically relevant neuronal populations, which constitute a technical challenge for analysis. Here, using a strategy that allows for ChIP-seq combined with RNA-seq in small neuronal populations in vivo, we present a comparative analysis of permissive and repressive histone modifications in adult midbrain dopaminergic neurons, raphe nuclei serotonergic neurons, and embryonic neural progenitors. Furthermore, we utilize the map generated by our analysis to show that the transcriptional response of midbrain dopaminergic neurons following 6-OHDA or methamphetamine injection is characterized by increased expression of genes with promoters dually marked by H3K4me3/H3K27me3. Our study provides an in vivo genome-wide analysis of permissive/repressive histone modifications coupled to gene expression in these rare neuronal subtypes.
Highlights
While single-cell RNA-sequencing technology has begun to delineate how neuronal subtypes in the adult brain are defined by unique patterns of gene expression[1], less is known about how stable long-term silencing of alternative lineages and progenitor genes is maintained to preserve subtype identity[2]
We show that dopaminergic stressinduced gene expression in a mouse model of Parkinson’s disease, or after methamphetamine injection, is characterized by derepression of genes with promoter regions dually marked by H3K4me[3] and H3K27me[3], whereas induction of genes with promoter regions marked by any other combination of H3K27me[3] and H3K9me[3] occurs less frequently
To understand how repression of neural progenitor cells (NPCs)-specific genes is reflected by the presence of the analyzed histone modifications in mDA neurons, we investigated transitions between chromatin states in NPCs and mDA neurons for genes downregulated in mDA relative to NPC
Summary
While single-cell RNA-sequencing technology has begun to delineate how neuronal subtypes in the adult brain are defined by unique patterns of gene expression[1], less is known about how stable long-term silencing of alternative lineages and progenitor genes is maintained to preserve subtype identity[2]. Increasing efforts have been directed to understand how aberrant neuronal gene regulation is involved in the etiology of neurodevelopmental, neurodegenerative, and mental disorders[3,4] Within this context, epigenetic mechanisms that facilitate regulation of chromatin structure, in particular through dynamic modification of histones, have gained much attention[3,4]. To overcome the obstacles related to heterogeneity and limited cell numbers, and investigate the association between histone modifications and subtype-specific gene expression, we adopted an approach that allowed us to generate several genome-wide ChIP-seqs combined with RNA-seq data from sparse neuronal subtypes from single adult mouse brains. We present a genome-wide comparison between permissive and repressive histone modifications correlated with gene expression in neural progenitor cells (NPCs) and two clinically relevant neuronal subtypes in vivo: mDA neurons and raphe nuclei serotonergic neurons (SER neurons). We show that dopaminergic stressinduced gene expression in a mouse model of Parkinson’s disease, or after methamphetamine injection, is characterized by derepression of genes with promoter regions dually marked by H3K4me[3] and H3K27me[3], whereas induction of genes with promoter regions marked by any other combination of H3K27me[3] and H3K9me[3] occurs less frequently
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