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Single cell epigenomic atlas of the developing human brain and organoids

Ryan S. Ziffra, Chang N. Kim, Amy Wilfert, Maximilian Haeussler, Alex M. Casella, Pawel F. Przytycki, Anat Kreimer, Katherine S. Pollard, Seth A. Ament, Evan E. Eichler, Nadav Ahituv, Tomasz J. Nowakowski
doi: https://doi.org/10.1101/2019.12.30.891549
Ryan S. Ziffra
1Department of Anatomy, University of California, San Francisco, CA, USA
2Department of Psychiatry, University of California, San Francisco, CA, USA
3Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
4Institute for Human Genetics, University of California, San Francisco, CA, USA
5Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Chang N. Kim
1Department of Anatomy, University of California, San Francisco, CA, USA
2Department of Psychiatry, University of California, San Francisco, CA, USA
3Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
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Amy Wilfert
6Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
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Maximilian Haeussler
7Genomics Institute, University of California, Santa Cruz, CA, USA
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Alex M. Casella
8Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD
9Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, MD
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Pawel F. Przytycki
10Gladstone Institutes, San Francisco, CA, USA
11Institute for Computational Health Sciences, University of California, San Francisco, CA, USA
12Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
13Quantitative Biology Institute, University of California, San Francisco, CA, USA
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Anat Kreimer
4Institute for Human Genetics, University of California, San Francisco, CA, USA
5Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
14Department of Electrical Engineering and Computer Sciences and Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA
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Katherine S. Pollard
10Gladstone Institutes, San Francisco, CA, USA
11Institute for Computational Health Sciences, University of California, San Francisco, CA, USA
12Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
13Quantitative Biology Institute, University of California, San Francisco, CA, USA
15Chan Zuckerberg Biohub, San Francisco, CA, USA
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Seth A. Ament
8Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD
16Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD
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Evan E. Eichler
6Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
17Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
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Nadav Ahituv
4Institute for Human Genetics, University of California, San Francisco, CA, USA
5Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
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Tomasz J. Nowakowski
1Department of Anatomy, University of California, San Francisco, CA, USA
2Department of Psychiatry, University of California, San Francisco, CA, USA
3Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
15Chan Zuckerberg Biohub, San Francisco, CA, USA
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  • For correspondence: tomasz.nowakowski@ucsf.edu
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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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Posted December 31, 2019.
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Single cell epigenomic atlas of the developing human brain and organoids
Ryan S. Ziffra, Chang N. Kim, Amy Wilfert, Maximilian Haeussler, Alex M. Casella, Pawel F. Przytycki, Anat Kreimer, Katherine S. Pollard, Seth A. Ament, Evan E. Eichler, Nadav Ahituv, Tomasz J. Nowakowski
bioRxiv 2019.12.30.891549; doi: https://doi.org/10.1101/2019.12.30.891549
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Single cell epigenomic atlas of the developing human brain and organoids
Ryan S. Ziffra, Chang N. Kim, Amy Wilfert, Maximilian Haeussler, Alex M. Casella, Pawel F. Przytycki, Anat Kreimer, Katherine S. Pollard, Seth A. Ament, Evan E. Eichler, Nadav Ahituv, Tomasz J. Nowakowski
bioRxiv 2019.12.30.891549; doi: https://doi.org/10.1101/2019.12.30.891549

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