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 |
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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 |
format | Article |
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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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03209-8</identifier><identifier>PMID: 34616060</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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</subject><ispartof>Nature (London), 2021-10, Vol.598 (7879), p.205-213</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>Copyright Nature Publishing Group Oct 7, 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-21d98a94655e8eb6cdc095a95f2b4ce7d4d91198615d9071c61dea3abcd75aa03</citedby><cites>FETCH-LOGICAL-c474t-21d98a94655e8eb6cdc095a95f2b4ce7d4d91198615d9071c61dea3abcd75aa03</cites><orcidid>0000-0001-8590-222X ; 0000-0003-2345-4964 ; 0000-0002-8246-4014 ; 0000-0001-8246-6477 ; 0000-0001-8721-8253 ; 0000-0002-7434-8144 ; 0000-0002-7481-0511 ; 0000-0001-6443-7509 ; 0000-0002-9870-6196 ; 0000-0002-3360-6936</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03209-8$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03209-8$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34616060$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ziffra, Ryan S.</creatorcontrib><creatorcontrib>Kim, Chang N.</creatorcontrib><creatorcontrib>Ross, Jayden M.</creatorcontrib><creatorcontrib>Wilfert, Amy</creatorcontrib><creatorcontrib>Turner, Tychele N.</creatorcontrib><creatorcontrib>Haeussler, Maximilian</creatorcontrib><creatorcontrib>Casella, Alex M.</creatorcontrib><creatorcontrib>Przytycki, Pawel F.</creatorcontrib><creatorcontrib>Keough, Kathleen C.</creatorcontrib><creatorcontrib>Shin, David</creatorcontrib><creatorcontrib>Bogdanoff, Derek</creatorcontrib><creatorcontrib>Kreimer, Anat</creatorcontrib><creatorcontrib>Pollard, Katherine S.</creatorcontrib><creatorcontrib>Ament, Seth A.</creatorcontrib><creatorcontrib>Eichler, Evan E.</creatorcontrib><creatorcontrib>Ahituv, Nadav</creatorcontrib><creatorcontrib>Nowakowski, Tomasz J.</creatorcontrib><title>Single-cell epigenomics reveals mechanisms of human cortical development</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><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.
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Elements, Genetic</subject><subject>Epigenomics</subject><subject>Forebrain</subject><subject>Gene expression</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>multidisciplinary</subject><subject>Neural stem cells</subject><subject>Neurodevelopmental disorders</subject><subject>Neurogenesis</subject><subject>Neurons - cytology</subject><subject>Neurons - metabolism</subject><subject>Organoids</subject><subject>Organoids - cytology</subject><subject>Prefrontal cortex</subject><subject>Progenitor cells</subject><subject>Regulatory sequences</subject><subject>Retinoic acid</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Single-Cell Analysis</subject><subject>Specifications</subject><subject>Transcription factors</subject><subject>Transposase</subject><subject>Tretinoin - 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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> |
fulltext | fulltext |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T04%3A36%3A29IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Single-cell%20epigenomics%20reveals%20mechanisms%20of%20human%20cortical%20development&rft.jtitle=Nature%20(London)&rft.au=Ziffra,%20Ryan%20S.&rft.date=2021-10-07&rft.volume=598&rft.issue=7879&rft.spage=205&rft.epage=213&rft.pages=205-213&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03209-8&rft_dat=%3Cproquest_pubme%3E2580025980%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2581019434&rft_id=info:pmid/34616060&rfr_iscdi=true |