. 2021 Sep 16;184(19):5053-5069.e23.

doi: 10.1016/j.cell.2021.07.039. Epub 2021 Aug 13.

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

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

Free article

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

Alexandro E Trevino et al. Cell. 2021.

Free article

. 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.

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Conflict of interest statement

Declaration of interests W.J.G. was 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 and Boundless Bio and an advisor of 10x Genomics, Arsenal Biosciences, and Spring Discovery. A.S. is an employee of Insitro, Inc, and receives consulting fees from Myokardia, Inc. K.F. is an employee of Illumina, Inc.

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

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

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