Cell Type-Specific Whole-Genome Landscape of DFOSB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure

摘要

BACKGROUND: The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor AFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of AFOSB's gene targets has not yet been generated.METHODS: We used CUT RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in AFOSB binding in the 2 main types of nucleus accumbens neurons-D1 or D2 medium spiny neurons-after chronic cocaine exposure. To annotate genomic regions of AFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses.RESULTS: The majority of AFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with AFOSB peaks, a finding consistent with earlier studies of AFOSB's interacting proteins. Chronic cocaine use induces broad changes in AFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that AFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors.CONCLUSIONS: These novel findings uncover key elements of AFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of AFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of AFOSB and the molecular basis of drug addiction.