Cell ( IF 64.5 ) Pub Date : 2021-08-13 , DOI: 10.1016/j.cell.2021.07.039 Alexandro E Trevino 1 , Fabian Müller 2 , Jimena Andersen 3 , Laksshman Sundaram 4 , Arwa Kathiria 1 , Anna Shcherbina 5 , Kyle Farh 6 , Howard Y Chang 7 , Anca M Pașca 8 , Anshul Kundaje 9 , Sergiu P Pașca 3 , William J Greenleaf 10
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.
中文翻译:
单细胞分辨率下发育中的人类大脑皮层的染色质和基因调控动力学
皮质发育的遗传扰动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,我们绘制了基因调控元件的活性,以独立和联合生成基因表达和染色质可及性的单细胞图谱。这揭示了关键转录因子 (TF) 在几乎连续的分化轨迹上的基因调控波,区分了神经胶质谱系的表达程序,并确定了在相关基因调控元件和表达水平之间表现出强相关性的谱系决定 TF。这些高度连接的基因在早期分化细胞中采用活跃的染色质状态,与谱系承诺一致。碱基对分辨率神经网络模型确定了非编码突变的强细胞类型特异性富集,这些突变预测在 ASD 个体队列中具有破坏性,并确定了经常被破坏的 TF 结合位点。这种方法说明了细胞类型特异性映射如何提供对人类发育和疾病管理计划的见解。