Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution
Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution
复制标题
DOI：
10.1016/j.cell.2021.07.039
复制
发表时间：
2021-09-16
期刊：
影响因子：
64.5
通讯作者：
Greenleaf, William J.
中科院分区：
文献类型：
--
作者：
Trevino, Alexandro E.;Mueller, Fabian;Greenleaf, William J.
皮质发育的遗传干扰可导致神经发育疾病，包括自闭症谱系障碍（ASD）。为了确定对皮质生成至关重要的基因组区域，我们绘制了基因调控元件的活性，产生了基因表达和染色质可及性的单细胞图谱，包括独立和联合图谱。这揭示了关键转录因子（TF）在几乎连续的分化轨迹中的基因调控波，区分了神经胶质细胞谱系的表达程序，并确定了谱系决定TF，这些TF在相关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的细胞中采用了活跃的染色质状态，与谱系定型一致。碱基对分辨率神经网络模型确定了强细胞类型特异性富集的非编码突变预测是破坏性的ASD个体的队列，并确定了经常中断TF结合位点。这种方法说明了细胞类型特异性映射如何为人类发育和疾病的管理程序提供见解。
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.