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

Alexandro E Trevino; Fabian Müller; Jimena Andersen; Laksshman Sundaram; Arwa Kathiria; Anna Shcherbina; Kyle Farh; Howard Y Chang; Anca M Pașca; Anshul Kundaje; Sergiu P Pașca; William J Greenleaf

doi:10.1016/j.cell.2021.07.039

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

Cell. 2021 Sep 16;184(19):5053-5069.e23. doi: 10.1016/j.cell.2021.07.039. Epub 2021 Aug 13.

Authors

Affiliations

¹ Department of Genetics, Stanford University, Stanford, CA, USA.
² Department of Genetics, Stanford University, Stanford, CA, USA; Center for Bioinformatics, Saarland University, Saarbrücken, Germany.
³ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; Stanford Brain Organogenesis Program, Wu Tsai Neuroscience Institute Stanford University, Stanford, CA, USA.
⁴ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁵ Biomedical Data Science Program, Stanford University, Stanford CA, USA.
⁶ Illumina Artificial Intelligence Laboratory, Illumina Inc, San Diego, CA, USA.
⁷ Department of Genetics, Stanford University, Stanford, CA, USA; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
⁸ Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA, USA.
⁹ Department of Genetics, Stanford University, Stanford, CA, USA; Department of Computer Science, Stanford University, Stanford, CA, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; Stanford Brain Organogenesis Program, Wu Tsai Neuroscience Institute Stanford University, Stanford, CA, USA. Electronic address: spasca@stanford.edu.
¹¹ Department of Genetics, Stanford University, Stanford, CA, USA; Department of Applied Physics, Stanford University, Stanford, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA. Electronic address: wjg@stanford.edu.

PMID: 34390642
DOI: 10.1016/j.cell.2021.07.039

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 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.

Keywords: autism spectrum disoder; development; human cerebral cortex; multiome; single-cell ATAC-seq; single-cell RNA-seq.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Astrocytes / cytology
Cell Differentiation
Cell Lineage / genetics
Cerebral Cortex / embryology*
Chromatin / metabolism*
Cluster Analysis
Deep Learning
Epigenesis, Genetic
Fuzzy Logic
Gene Expression Regulation, Developmental*
Glutamates / metabolism
Humans
Mutation / genetics
Neurons / metabolism
Regulatory Sequences, Nucleic Acid / genetics
Single-Cell Analysis*

Substances

Chromatin
Glutamates