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

Trevino, A. E.; Muller, F.; Andersen, J.; Sundaram, L.; Kathiria, A.; Shcherbina, A.; Farh, K.; Chang, H. Y.; Pasca, A. M.; Kundaje, A.; Pasca, S. P.; Greenleaf, W. J.

doi:10.1101/2020.12.29.424636

bioRxiv · 10.1101/2020.12.29.424636

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

Trevino, A. E.·Muller, F.·Andersen, J.·Sundaram, L.·Kathiria, A.·Shcherbina, A.·Farh, K.·Chang, H. Y.·Pasca, A. M.·Kundaje, A.·Pasca, S. P.·Greenleaf, W. J.

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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.

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Trevino, A. E., Muller, F., Andersen, J., Sundaram, L., Kathiria, A., Shcherbina, A., Farh, K., Chang, H. Y., Pasca, A. M., Kundaje, A., Pasca, S. P., Greenleaf, W. J.. 2020-12-30. Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution. https://doi.org/10.1101/2020.12.29.424636

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