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

• Published in: bioRxiv
• Main Authors: Trevino, Alexandro E, Müller, Fabian, Andersen, Jimena, Sundaram, Laksshman, Kathiria, Arwa, Shcherbina, Anna, Farh, Kyle, Chang, Howard Y, Paşca, Anca M, Kundaje, Anshul, Paşca, Sergiu P, Greenleaf, William J
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 01.01.2021; Cold Spring Harbor Laboratory
• Edition: 1.2
• Subjects: Autism; Binding sites; Cell culture; Cell differentiation; Cerebral cortex; Chromatin; Gene expression; Gene mapping; Gene regulation; Genomics; Glutamatergic transmission; Neural networks; Neurodevelopmental disorders; Neuronal-glial interactions; Neuroscience; Regulatory sequences; Transcription factors
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2020.12.29.424636

ABSTRACT Genetic perturbations of cerebral 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 into glutamatergic neurons, 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. Basepair-resolution neural network models identified strong cell-type specific enrichment of noncoding mutations predicted to be disruptive in a cohort of ASD subjects 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. Competing Interest Statement WJG is a consultant for 10x Genomics and is named as an inventor on patents describing ATAC-seq methods. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and an advisor of 10x Genomics, Arsenal Biosciences, and Spring Discovery. A. Shcherbina is an employee of Insitro, Inc and receives consulting fees from Myokardia, Inc.