Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell, 2021-09, Vol.184 (19), p.5053-5069.e23

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.