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, 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 used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB 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 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 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, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons 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 D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction.
Keywords: Addiction; CUT&RUN; ChIP-sequencing; Chromatin remodeling complex; Histone modifications; Nucleus accumbens; Transcription factor.
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