Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution

• Published in: Cell Vol. 184; no. 19; pp. 5053 - 5069.e23
• Main Authors: Trevino, Alexandro E., Müller, Fabian, Andersen, Jimena, Sundaram, Laksshman, Kathiria, Arwa, Shcherbina, Anna, Farh, Kyle, Chang, Howard Y., Pașca, Anca M., Kundaje, Anshul, Pașca, Sergiu P., Greenleaf, William J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.09.2021
• Subjects: Astrocytes - cytology; autism; autism spectrum disoder; Cell Differentiation; Cell Lineage - genetics; cerebral cortex; Cerebral Cortex - embryology; chromatin; Chromatin - metabolism; Cluster Analysis; Deep Learning; development; Epigenesis, Genetic; Fuzzy Logic; gene expression; Gene Expression Regulation, Developmental; genes; genomics; Glutamates - metabolism; human cerebral cortex; human development; Humans; multiome; Mutation - genetics; Neurons - metabolism; Regulatory Sequences, Nucleic Acid - genetics; Single-Cell Analysis; single-cell ATAC-seq; single-cell RNA-seq; human cerebral cortex; single-cell RNA-seq; development; single-cell ATAC-seq; autism spectrum disoder; multiome
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.07.039

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. [Display omitted] •Single-cell RNA and chromatin profiling charts human corticogenesis•Distinct TFs underlie neurogenesis and gliogenesis regulatory programs•Lineage-determining TFs adopt an active chromatin state early in differentiation•Neural networks prioritize noncoding de novo mutations in autism spectrum disorder A single-cell atlas of gene expression and chromatin accessibility of human developing cortex during mid-gestation reveals lineage-determining transcription factors for human corticogenesis and identifies prioritized mutations for autism spectrum disorder.