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

View ORCID ProfileAlexandro E. Trevino, View ORCID ProfileFabian Müller, View ORCID ProfileJimena Andersen, View ORCID ProfileLaksshman Sundaram, Arwa Kathiria, Anna Shcherbina, Kyle Farh, Howard Y. Chang, View ORCID ProfileAnca M. Paşca, View ORCID ProfileAnshul Kundaje, View ORCID ProfileSergiu P. Paşca, View ORCID ProfileWilliam J. Greenleaf
doi: https://doi.org/10.1101/2020.12.29.424636
Alexandro E. Trevino
1Department of Genetics, Stanford University, Stanford, CA, USA
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Fabian Müller
1Department of Genetics, Stanford University, Stanford, CA, USA
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  • ORCID record for Fabian Müller
Jimena Andersen
2Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
3Stanford Brain Organogenesis Program, Wu Tsai Neuroscience Institute, Stanford, CA, USA
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Laksshman Sundaram
4Department of Computer Science, Stanford University, Stanford, CA, USA
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Arwa Kathiria
1Department of Genetics, Stanford University, Stanford, CA, USA
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Anna Shcherbina
5Biomedical Data Science Program, Stanford University, Stanford CA, USA
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Kyle Farh
6Illumina Artificial Intelligence Laboratory, Illumina Inc, San Diego, CA, USA
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Howard Y. Chang
1Department of Genetics, Stanford University, Stanford, CA, USA
7Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA
8Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
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Anca M. Paşca
9Department of Pediatrics, Division of Neonatology, Stanford University, Stanford, CA, USA
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  • ORCID record for Anca M. Paşca
Anshul Kundaje
1Department of Genetics, Stanford University, Stanford, CA, USA
4Department of Computer Science, Stanford University, Stanford, CA, USA
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Sergiu P. Paşca
2Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
3Stanford Brain Organogenesis Program, Wu Tsai Neuroscience Institute, Stanford, CA, USA
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  • For correspondence: spasca@stanford.edu wjg@stanford.edu
William J. Greenleaf
1Department of Genetics, Stanford University, Stanford, CA, USA
10Department of Applied Physics, Stanford University, Stanford, CA, USA
11Chan–Zuckerberg Biohub, San Francisco, CA, USA
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  • For correspondence: spasca@stanford.edu wjg@stanford.edu
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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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 01, 2021.
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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. Paşca, Anshul Kundaje, Sergiu P. Paşca, William J. Greenleaf
bioRxiv 2020.12.29.424636; doi: https://doi.org/10.1101/2020.12.29.424636
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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. Paşca, Anshul Kundaje, Sergiu P. Paşca, William J. Greenleaf
bioRxiv 2020.12.29.424636; doi: https://doi.org/10.1101/2020.12.29.424636

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