Cited by 494Single-cell and spatial transcriptomicsGenomics and Chromatin DynamicsDevelopmental Biology and Gene Regulation

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

Open access
Trevino, Alexandro E., Müller, Fabian, Andersen, Jimena, Sundaram, Laksshman, Kathiria, Arwa, Shcherbina, Anna, Farh, Kyle, Chang, Howard Y. +4 more·2021·Cell

Published version of a preprint

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.

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Crossref · 10.1016/j.cell.2021.07.039

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  • Many autism spectrum disorder risk genes associated with transcriptional regulation and chromatin remodelling are crucial for cortical development.

    “Many ASD risk genes associated with transcriptional regulation and chromatin remodelling are crucial for cortical development21,22.”
  • The OLIG1 module was previously identified as crucial for oligodendrocyte differentiation in the developing human cortex.

    “This module was previously identified as crucial for oligodendrocyte differentiation in the developing human cortex22, highlighting the involvement of the oligodendrocytes in ASD pathophysiology.”
  • Single-cell multiomics allows uncovering mechanisms of gene regulation across different omics layers but lacks spatial information, which is crucial to understanding cellular function in tissue.

    “Single-cell multiomics allows uncovering of the mechanisms of gene regulation across different omics layers6–9 but lacks spatial information, which is crucial to understanding cellular function in tissue.”

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Authors
Trevino, A. E., Müller, F., Andersen, J., Sundaram, L., Kathiria, A., Shcherbina, A., Farh, K., Chang, H. Y., Pașca, A. M., Kundaje, A., Pașca, S. P., & Greenleaf, W. J.
Affiliations
  • Stanford University (US)
  • Saarland University (DE)
  • Stanford Medicine (US)
  • Illumina (United States) (US)
  • Howard Hughes Medical Institute (US)
  • Chan Zuckerberg Biohub San Francisco (US)
Corresponding author
  • Pașca, Sergiu P.
  • Greenleaf, William J.
Venue
Cell
Publisher
Elsevier BV
Published
2021-09
Volume
184
Issue
19
Pages
5053-5069.e23
ISSN
0092-8674 (ISSN-L)
OpenAlex
W3194509722
Cited by
478
References
78
Citations by year
2026: 76 · 2025: 99 · 2024: 110 · 2023: 99 · 2022: 75 · 2021: 17 · 2020: 1
FWCI
24.80
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
  • PubMed (publishedVersion)
Funders
Leland Stanford Junior University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
cortical development, chromatin accessibility, gene regulatory elements, single-cell atlas, transcription factors, lineage commitment, autism spectrum disorder, non-coding mutations, transcription factor binding sites, neural network model, neurodevelopmental disorders
MeSH terms
Deep Learning, Astrocytes, Cell Differentiation, Cerebral Cortex, Chromatin, Glutamates, Humans, Mutation, Neurons, Regulatory Sequences, Nucleic Acid, Cluster Analysis, Fuzzy Logic, Gene Expression Regulation, Developmental, Cell Lineage, Epigenesis, Genetic, Single-Cell Analysis

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