Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression in a cell-type-specific manner depending on the chromatin structure and accessibility. We report 20,658 single-nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell-type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell-type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Our data set provides an extensive resource to study gene regulation in mesencephalon and provides insights into control of cell identity in the midbrain and identifies cell-type-specific regulatory variation possibly underlying phenotypic and behavioural differences between mouse strains.

中文翻译：

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腹侧中脑的单核染色质分析揭示细胞身份转录因子和细胞类型特异性基因调控变异

腹侧中脑的细胞类型与遗传易感性不同的疾病有关，例如帕金森病和精神分裂症。许多遗传变异会影响调节区域并以细胞类型特异性方式改变基因表达，具体取决于染色质结构和可及性。我们报告了来自两个基因和表型不同的小鼠品系的腹侧中脑的 20,658 个单核染色质可及性配置文件。我们根据染色质谱区分十种细胞类型，对控制细胞身份基因的可及区域的分析突出了细胞类型特异性的关键转录因子。分离小鼠品系的调节变异更多地表现在转录组上而不是染色质水平上。然而，细胞类型水平的数据揭示了未在组织水平上捕获的变化。为了发现中脑基因表达中顺式作用变异的范围和细胞类型特异性，我们鉴定了推定的调节变体并显示它们在差异表达的基因座上富集。最后，我们发现 TCF7L2 选择性地介导中脑神经元中的反式作用变异。我们的数据集为研究中脑基因调控提供了广泛的资源，并提供了对中脑细胞特性控制的见解，并确定了细胞类型特异性调控变异可能是小鼠品系之间表型和行为差异的基础。