Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure

ABSTRACT: Background The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor, ΔFOSB, in the nucleus accumbens (NAc), a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB’s gene targets has not yet been generated. Methods We use CUT&RUN to map the genome-wide changes in ΔFOSB binding in the two main types of NAc neurons—D1 or D2 medium spiny neurons (MSNs)—after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses. Results The majority of ΔFOSB peaks occur outside of 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 ΔFOSB peaks, consistent with earlier studies of ΔFOSB’s interacting proteins. Chronic cocaine induces broad changes in ΔFOSB binding in both D1 and D2 NAc MSNs of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. Conclusions These novel findings uncover key elements of ΔFOSB’s molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB’s collaborative transcriptional and chromatin partners specifically in D1 and in D2 MSNs will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction.

ORGANISM(S): Mus musculus

PROVIDER: GSE197668 | GEO | 2022/07/08

REPOSITORIES: GEO