Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
Biol Psychiatry. 2023 Sep 1;94(5):367-377. doi: 10.1016/j.biopsych.2022.12.021. Epub 2023 Jan 2.
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.
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.
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.
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.
神经元对外界刺激做出反应的能力涉及基因表达的适应性变化。在大脑奖励区域伏隔核中，转录因子ΔFOSB 的诱导对于药物成瘾的发展很重要。然而，ΔFOSB 的基因靶点的综合图谱尚未生成。
我们使用 CUT&RUN（通过核酸酶在靶标下切割和释放）来绘制慢性可卡因暴露后 2 种主要的伏隔核神经元-D1 或 D2 中型多棘神经元中 ΔFOSB 结合的全基因组变化图谱。为了注释 ΔFOSB 结合位点的基因组区域，我们还检查了几种组蛋白修饰的分布。由此产生的数据集被用于多种生物信息学分析。
大多数 ΔFOSB 峰出现在启动子区域之外，包括基因间区域，并且被表示活跃增强子的表观遗传标记包围。BRG1 是 SWI/SNF 染色质重塑复合物的核心亚基，与 ΔFOSB 峰重叠，这与早期关于 ΔFOSB 相互作用蛋白的研究一致。慢性可卡因使用会诱导雄性和雌性小鼠伏隔核 D1 和 D2 中型多棘神经元中 ΔFOSB 结合的广泛变化。此外，计算机分析预测 ΔFOSB 与同源盒和 T 盒转录因子协同调节基因表达。
这些新发现揭示了 ΔFOSB 在转录调节中的基本分子机制，包括在基线和慢性可卡因暴露时的关键要素。进一步表征 ΔFOSB 与特定 D1 和 D2 中型多棘神经元中的转录和染色质伙伴的协同作用将揭示 ΔFOSB 的功能和药物成瘾的分子基础的更广泛图景。
