Single-cell epigenomics reveals mechanisms of human cortical development

During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape 1 . In the developing brain, cell fate specification and topographic identity are important for defining cell identity 2 and confer selective vulne...

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Veröffentlicht in:Nature (London) 2021-10, Vol.598 (7879), p.205-213
Hauptverfasser: Ziffra, Ryan S., Kim, Chang N., Ross, Jayden M., Wilfert, Amy, Turner, Tychele N., Haeussler, Maximilian, Casella, Alex M., Przytycki, Pawel F., Keough, Kathleen C., Shin, David, Bogdanoff, Derek, Kreimer, Anat, Pollard, Katherine S., Ament, Seth A., Eichler, Evan E., Ahituv, Nadav, Nowakowski, Tomasz J.
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container_end_page 213
container_issue 7879
container_start_page 205
container_title Nature (London)
container_volume 598
creator Ziffra, Ryan S.
Kim, Chang N.
Ross, Jayden M.
Wilfert, Amy
Turner, Tychele N.
Haeussler, Maximilian
Casella, Alex M.
Przytycki, Pawel F.
Keough, Kathleen C.
Shin, David
Bogdanoff, Derek
Kreimer, Anat
Pollard, Katherine S.
Ament, Seth A.
Eichler, Evan E.
Ahituv, Nadav
Nowakowski, Tomasz J.
description During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape 1 . In the developing brain, cell fate specification and topographic identity are important for defining cell identity 2 and confer selective vulnerabilities to neurodevelopmental disorders 3 . Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. 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. Analysis of chromatin state at a single-cell level in samples of developing human forebrain demonstrate both cell-type-specific and region-specific changes during neurogenesis.
doi_str_mv 10.1038/s41586-021-03209-8
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Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. 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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Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ziffra, Ryan S.</au><au>Kim, Chang N.</au><au>Ross, Jayden M.</au><au>Wilfert, Amy</au><au>Turner, Tychele N.</au><au>Haeussler, Maximilian</au><au>Casella, Alex M.</au><au>Przytycki, Pawel F.</au><au>Keough, Kathleen C.</au><au>Shin, David</au><au>Bogdanoff, Derek</au><au>Kreimer, Anat</au><au>Pollard, Katherine S.</au><au>Ament, Seth A.</au><au>Eichler, Evan E.</au><au>Ahituv, Nadav</au><au>Nowakowski, Tomasz J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-cell epigenomics reveals mechanisms of human cortical development</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-10-07</date><risdate>2021</risdate><volume>598</volume><issue>7879</issue><spage>205</spage><epage>213</epage><pages>205-213</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape 1 . In the developing brain, cell fate specification and topographic identity are important for defining cell identity 2 and confer selective vulnerabilities to neurodevelopmental disorders 3 . Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. 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. Analysis of chromatin state at a single-cell level in samples of developing human forebrain demonstrate both cell-type-specific and region-specific changes during neurogenesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34616060</pmid><doi>10.1038/s41586-021-03209-8</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-8590-222X</orcidid><orcidid>https://orcid.org/0000-0003-2345-4964</orcidid><orcidid>https://orcid.org/0000-0002-8246-4014</orcidid><orcidid>https://orcid.org/0000-0001-8246-6477</orcidid><orcidid>https://orcid.org/0000-0001-8721-8253</orcidid><orcidid>https://orcid.org/0000-0002-7434-8144</orcidid><orcidid>https://orcid.org/0000-0002-7481-0511</orcidid><orcidid>https://orcid.org/0000-0001-6443-7509</orcidid><orcidid>https://orcid.org/0000-0002-9870-6196</orcidid><orcidid>https://orcid.org/0000-0002-3360-6936</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0028-0836
ispartof Nature (London), 2021-10, Vol.598 (7879), p.205-213
issn 0028-0836
1476-4687
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8494642
source MEDLINE; SpringerLink Journals; Nature Journals Online
subjects 13/51
38/35
45/47
45/91
631/136/368/2430
631/378/2571/2575
96/100
Accessibility
Atlases as Topic
Binding sites
Brain
Brain - cytology
Brain - growth & development
Brain - metabolism
Cell fate
Cells (biology)
Cerebral cortex
Chromatin
Chromatin - chemistry
Chromatin - genetics
Chromatin - metabolism
Datasets
Differentiation (biology)
Disease Susceptibility
Enhancer Elements, Genetic
Epigenomics
Forebrain
Gene expression
Humanities and Social Sciences
Humans
multidisciplinary
Neural stem cells
Neurodevelopmental disorders
Neurogenesis
Neurons - cytology
Neurons - metabolism
Organoids
Organoids - cytology
Prefrontal cortex
Progenitor cells
Regulatory sequences
Retinoic acid
Science
Science (multidisciplinary)
Single-Cell Analysis
Specifications
Transcription factors
Transposase
Tretinoin - metabolism
title Single-cell epigenomics reveals mechanisms of human cortical development
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