2021年8月13日，美国斯坦福大学William J. Greenleaf、Sergiu P. Pa?ca等研究人员合作在《细胞》杂志发表论文，揭示单细胞分辨率下发育中人类大脑皮层的染色质和基因调控动态变化。
为了确定对皮层发育至关重要的基因组区域，研究人员绘制了基因调控元件的活性图谱，生成了一个独立和联合的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）在几乎连续分化轨迹中的基因调控浪潮，区分了胶质细胞系的表达程序，并确定了决定细胞系的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。
这些高度关联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。碱基分辨率的神经网络模型确定了非编码突变在自闭症谱系障碍（ASD）个体队列中的强烈细胞类型特异性富集，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图谱如何能够提供对人类发育和疾病管理程序的洞察。
据介绍，皮层发育的遗传紊乱可导致神经发育疾病，包括ASD。
附：英文原文
Title: Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution
Author: Alexandro E. Trevino, Fabian Müller, Jimena Andersen, Laksshman Sundaram, Arwa Kathiria, Anna Shcherbina, Kyle Farh, Howard Y. Chang, Anca M. Paca, Anshul Kundaje, Sergiu P. Paca, William J. Greenleaf
Issue&Volume: 2021-08-13
Abstract: 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 atlasof gene expression and chromatin accessibility both independently and jointly. Thisrevealed waves of gene regulation by key transcription factors (TFs) across a nearlycontinuous differentiation trajectory, distinguished the expression programs of gliallineages, and identified lineage-determining TFs that exhibited strong correlationbetween linked gene-regulatory elements and expression levels. These highly connectedgenes adopted an active chromatin state in early differentiating cells, consistentwith lineage commitment. Base-pair-resolution neural network models identified strongcell-type-specific enrichment of noncoding mutations predicted to be disruptive ina cohort of ASD individuals and identified frequently disrupted TF binding sites.This approach illustrates how cell-type-specific mapping can provide insights intothe programs governing human development and disease.
DOI: 10.1016/j.cell.2021.07.039
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00942-9