PreprintCited by 33Single-cell and spatial transcriptomicsGenomics and Chromatin DynamicsNeurogenesis and neuroplasticity mechanisms

Single cell epigenomic atlas of the developing human brain and organoids

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Ziffra, Ryan S., Kim, Chang N., Wilfert, Amy, Turner, Tychele N., Haeussler, Maximilian, Casella, Alex M., Przytycki, Pawel F., Kreimer, Anat +5 more·2019·bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Dynamic changes in chromatin accessibility coincide with important aspects of neuronal differentiation, such as fate specification and arealization and confer cell type-specific associations to neurodevelopmental disorders. However, studies of the epigenomic landscape of the developing human brain have yet to be performed at single-cell resolution. Here, we profiled chromatin accessibility of >75,000 cells from eight distinct areas of developing human forebrain using single cell ATAC-seq (scATACseq). We identified thousands of loci that undergo extensive cell type-specific changes in accessibility during corticogenesis. Chromatin state profiling also reveals novel distinctions between neural progenitor cells from different cortical areas not seen in transcriptomic profiles and suggests a role for retinoic acid signaling in cortical arealization. Comparison of the cell type-specific chromatin landscape of cerebral organoids to primary developing cortex found that organoids establish broad cell type-specific enhancer accessibility patterns similar to the developing cortex, but lack many putative regulatory elements identified in homologous primary cell types. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.

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Crossref · 10.1101/2019.12.30.891549

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  • Cellular heterogeneity in the human brain poses significant challenges for unraveling the gene regulatory architecture because the brain comprises heterogeneous cell populations with distinct gene expression and chromatin accessibility profiles.

    “However, cellular heterogeneity poses significant challenges for unraveling the complexity in the gene regulatory architecture of the human brain, as it is comprised of heterogeneous cell populations, mostly different types of neurons and glia, each of which display distinct gene expression3,8–10 and chromatin accessibility profiles11–14.”

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Authors
Ziffra, R. S., Kim, C. N., Wilfert, A., Turner, T. N., Haeussler, M., Casella, A. M., Przytycki, P. F., Kreimer, A., Pollard, K. S., Ament, S. A., Eichler, E. E., Ahituv, N., & Nowakowski, T. J.
Affiliations
  • University of California, San Francisco (US)
  • University of Washington (US)
  • Washington University in St. Louis (US)
  • University of California, Santa Cruz (US)
  • University of Maryland, Baltimore (US)
  • Gladstone Institutes (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Nowakowski, Tomasz J.
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2019-12-31
OpenAlex
W2998343721
Cited by
33
References
88
Citations by year
2025: 1 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 11 · 2020: 11 · 2019: 1
Type
posted content
Language
en
Open access
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
  • Autism Speaks
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health
  • National Institute of Mental Health (1K99MH117165, U01MH115747, U01MH114825, U01MH116438)
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 › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
chromatin accessibility, human brain development, forebrain, cortical development, neural progenitor cells, retinoic acid signaling, brain organoids, enhancer accessibility, cell fate specification, neurodevelopmental disorders, single-cell epigenomics

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