Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun. 2024 Nov 22;15(1):10113. doi: 10.1038/s41467-024-54448-y.
Brain region- and cell-specific transcriptomic and epigenomic features are associated with heritability for neuropsychiatric traits, but a systematic view, considering cortical and subcortical regions, is lacking. Here, we provide an atlas of chromatin accessibility and gene expression profiles in neuronal and non-neuronal nuclei across 25 distinct human cortical and subcortical brain regions from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions, including variation in alternative promoter-isoform usage and enhancer-promoter interactions. Genes with distinct promoter-isoform usage across brain regions were strongly enriched for neuropsychiatric disease risk variants. Moreover, we built enhancer-promoter interactions at promoter-isoform resolution across different brain regions and highlighted the contribution of brain region-specific and promoter-isoform-specific regulation to neuropsychiatric disorders. Including promoter-isoform resolution uncovers additional distal elements implicated in the heritability of diseases, thereby increasing the power to fine-map risk genes. Our results provide a valuable resource for studying molecular regulation across multiple regions of the human brain and underscore the importance of considering isoform information in gene regulation.
大脑区域和细胞特异性转录组和表观基因组特征与神经精神特征的遗传性有关，但缺乏系统的观点，同时考虑皮质和皮质下区域。在这里，我们提供了一个图谱，展示了 25 个不同的人类皮质和皮质下脑区的 6 个神经正常对照个体的神经元和非神经元核中的染色质可及性和基因表达谱。我们发现了大脑区域之间广泛的基因表达和染色质可及性差异，包括不同启动子亚型的使用和增强子-启动子相互作用的变化。在大脑区域之间具有不同启动子亚型使用的基因强烈富集了神经精神疾病风险变异。此外，我们在不同脑区的启动子亚型分辨率上构建了增强子-启动子相互作用，并强调了脑区特异性和启动子亚型特异性调节对神经精神疾病的贡献。包括启动子亚型分辨率可以揭示疾病遗传性中涉及的其他远端元件，从而提高精细映射风险基因的能力。我们的研究结果为研究人类大脑多个区域的分子调节提供了有价值的资源，并强调了在基因调节中考虑异构体信息的重要性。
