Single cell epigenomic atlas of the developing human brain and organoids
Open accessAbstract
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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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.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [13]
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Single-cell analysis of prenatal and postnatal human cortical development
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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.
- ORCID
- 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
- green
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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