Department of Genetics, Stanford University, Stanford, CA, USA.
Department of Genetics, Stanford University, Stanford, CA, USA; Center for Bioinformatics, Saarland University, Saarbrücken, Germany.
Cell. 2021 Sep 16;184(19):5053-5069.e23. doi: 10.1016/j.cell.2021.07.039. Epub 2021 Aug 13.
Genetic perturbations of cortical development can lead to neurodevelopmental disease, including autism spectrum disorder (ASD). To identify genomic regions crucial to corticogenesis, we mapped the activity of gene-regulatory elements generating a single-cell atlas of gene expression and chromatin accessibility both independently and jointly. This revealed waves of gene regulation by key transcription factors (TFs) across a nearly continuous differentiation trajectory, distinguished the expression programs of glial lineages, and identified lineage-determining TFs that exhibited strong correlation between linked gene-regulatory elements and expression levels. These highly connected genes adopted an active chromatin state in early differentiating cells, consistent with lineage commitment. Base-pair-resolution neural network models identified strong cell-type-specific enrichment of noncoding mutations predicted to be disruptive in a cohort of ASD individuals and identified frequently disrupted TF binding sites. This approach illustrates how cell-type-specific mapping can provide insights into the programs governing human development and disease.
遗传干扰皮层发育可导致神经发育疾病，包括自闭症谱系障碍（ASD）。为了确定对皮质发生至关重要的基因组区域，我们对基因调控元件的活性进行了作图，这些元件生成了单细胞基因表达和染色质可及性图谱，独立和联合使用。这揭示了关键转录因子（TF）在近乎连续的分化轨迹上进行基因调控的波，区分了神经胶质谱系的表达程序，并确定了谱系决定 TF，这些 TF 在连接的基因调控元件和表达水平之间表现出强烈的相关性。这些高度连接的基因在早期分化细胞中呈现出活跃的染色质状态，与谱系决定一致。碱基分辨率神经网络模型鉴定了非编码突变的强烈细胞类型特异性富集，这些突变在 ASD 个体的队列中预测具有破坏性，并鉴定了经常被破坏的 TF 结合位点。这种方法说明了细胞类型特异性作图如何为人类发育和疾病的调控程序提供见解。
