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A Chromatin Accessibility Atlas of the Developing Human Telencephalon
To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers...
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| Published in: | Cell 2020-08, Vol.182 (3), p.754-769.e18 |
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| creator | Markenscoff-Papadimitriou, Eirene Whalen, Sean Przytycki, Pawel Thomas, Reuben Binyameen, Fadya Nowakowski, Tomasz J. Kriegstein, Arnold R. Sanders, Stephan J. State, Matthew W. Pollard, Katherine S. Rubenstein, John L. |
| description | To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.
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•∼19,000 enhancers defined in nine regions of the developing human telencephalon•Chromatin dynamics correlate with sequence motifs and spatiotemporal gene expression•Identified cortical layer-specific enhancers and validated a layer 5 FEZF2 enhancer•Genetic variants from patients alter activity of an enhancer for an autism risk gene
A high-resolution atlas of regulatory elements driving regional, temporal, and laminar gene expression programs in the developing human telencephalon reveals enhancers and genetic variants regulating human disease genes. |
| doi_str_mv | 10.1016/j.cell.2020.06.002 |
| format | article |
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[Display omitted]
•∼19,000 enhancers defined in nine regions of the developing human telencephalon•Chromatin dynamics correlate with sequence motifs and spatiotemporal gene expression•Identified cortical layer-specific enhancers and validated a layer 5 FEZF2 enhancer•Genetic variants from patients alter activity of an enhancer for an autism risk gene
A high-resolution atlas of regulatory elements driving regional, temporal, and laminar gene expression programs in the developing human telencephalon reveals enhancers and genetic variants regulating human disease genes.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2020.06.002</identifier><identifier>PMID: 32610082</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; ATAC-seq ; autism ; Autistic Disorder - genetics ; Cell Line ; chromatin ; Chromatin - genetics ; Chromatin - metabolism ; Chromatin Immunoprecipitation Sequencing ; Enhancer Elements, Genetic ; enhancers ; Euchromatin - genetics ; GABA Plasma Membrane Transport Proteins - genetics ; Gene Expression Regulation, Developmental - genetics ; Gene Ontology ; gene regulation ; Genetic Predisposition to Disease ; Gestational Age ; Humans ; machine learning ; Mice ; Mice, Transgenic ; neurodevelopment ; neuropsychiatric disorders ; Nucleotide Motifs ; Point Mutation ; Prefrontal Cortex - embryology ; Prefrontal Cortex - metabolism ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Spatio-Temporal Analysis ; Telencephalon - embryology ; Telencephalon - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Cell, 2020-08, Vol.182 (3), p.754-769.e18</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c521t-7cd4b9483042cdd1d72db7d7105ddc5bec5ffb4c14e9c68f838af856cc3331a23</citedby><cites>FETCH-LOGICAL-c521t-7cd4b9483042cdd1d72db7d7105ddc5bec5ffb4c14e9c68f838af856cc3331a23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32610082$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Markenscoff-Papadimitriou, Eirene</creatorcontrib><creatorcontrib>Whalen, Sean</creatorcontrib><creatorcontrib>Przytycki, Pawel</creatorcontrib><creatorcontrib>Thomas, Reuben</creatorcontrib><creatorcontrib>Binyameen, Fadya</creatorcontrib><creatorcontrib>Nowakowski, Tomasz J.</creatorcontrib><creatorcontrib>Kriegstein, Arnold R.</creatorcontrib><creatorcontrib>Sanders, Stephan J.</creatorcontrib><creatorcontrib>State, Matthew W.</creatorcontrib><creatorcontrib>Pollard, Katherine S.</creatorcontrib><creatorcontrib>Rubenstein, John L.</creatorcontrib><title>A Chromatin Accessibility Atlas of the Developing Human Telencephalon</title><title>Cell</title><addtitle>Cell</addtitle><description>To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.
[Display omitted]
•∼19,000 enhancers defined in nine regions of the developing human telencephalon•Chromatin dynamics correlate with sequence motifs and spatiotemporal gene expression•Identified cortical layer-specific enhancers and validated a layer 5 FEZF2 enhancer•Genetic variants from patients alter activity of an enhancer for an autism risk gene
A high-resolution atlas of regulatory elements driving regional, temporal, and laminar gene expression programs in the developing human telencephalon reveals enhancers and genetic variants regulating human disease genes.</description><subject>Animals</subject><subject>ATAC-seq</subject><subject>autism</subject><subject>Autistic Disorder - genetics</subject><subject>Cell Line</subject><subject>chromatin</subject><subject>Chromatin - genetics</subject><subject>Chromatin - metabolism</subject><subject>Chromatin Immunoprecipitation Sequencing</subject><subject>Enhancer Elements, Genetic</subject><subject>enhancers</subject><subject>Euchromatin - genetics</subject><subject>GABA Plasma Membrane Transport Proteins - genetics</subject><subject>Gene Expression Regulation, Developmental - genetics</subject><subject>Gene Ontology</subject><subject>gene regulation</subject><subject>Genetic Predisposition to Disease</subject><subject>Gestational Age</subject><subject>Humans</subject><subject>machine learning</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>neurodevelopment</subject><subject>neuropsychiatric disorders</subject><subject>Nucleotide Motifs</subject><subject>Point Mutation</subject><subject>Prefrontal Cortex - embryology</subject><subject>Prefrontal Cortex - metabolism</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Spatio-Temporal Analysis</subject><subject>Telencephalon - embryology</subject><subject>Telencephalon - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kE1r3DAQhkVpaLZJ_0APxcde7OrTsqEUlm2aFAK5JGchj8ZZLbK1lbwL-fex2TS0l5zEoOd9Z3gI-cxoxSirv-0qwBAqTjmtaF1Ryt-RFaOtLiXT_D1ZUdrysqm1PCcfc95RShul1AdyLnjN5oGvyNW62GxTHOzkx2INgDn7zgc_PRXrKdhcxL6Ytlj8xCOGuPfjY3FzGOxY3GPAEXC_tSGOl-SstyHjp5f3gjz8urrf3JS3d9e_N-vbEhRnU6nBya6VjaCSg3PMae467TSjyjlQHYLq-04Ck9hC3fSNaGzfqBpACMEsFxfkx6l3f-gGdIDjlGww--QHm55MtN78_zP6rXmMR6MlU7Vu5oKvLwUp_jlgnszg82LRjhgP2XDJWs1EKxaUn1BIMeeE_esaRs3i3-zMkjSLf0NrM_ufQ1_-PfA18lf4DHw_AThrOnpMJoNfRDqfECbjon-r_xm-KJf_</recordid><startdate>20200806</startdate><enddate>20200806</enddate><creator>Markenscoff-Papadimitriou, Eirene</creator><creator>Whalen, Sean</creator><creator>Przytycki, Pawel</creator><creator>Thomas, Reuben</creator><creator>Binyameen, Fadya</creator><creator>Nowakowski, Tomasz J.</creator><creator>Kriegstein, Arnold R.</creator><creator>Sanders, Stephan J.</creator><creator>State, Matthew W.</creator><creator>Pollard, Katherine S.</creator><creator>Rubenstein, John L.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200806</creationdate><title>A Chromatin Accessibility Atlas of the Developing Human Telencephalon</title><author>Markenscoff-Papadimitriou, Eirene ; Whalen, Sean ; Przytycki, Pawel ; Thomas, Reuben ; Binyameen, Fadya ; Nowakowski, Tomasz J. ; Kriegstein, Arnold R. ; Sanders, Stephan J. ; State, Matthew W. ; Pollard, Katherine S. ; Rubenstein, John L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c521t-7cd4b9483042cdd1d72db7d7105ddc5bec5ffb4c14e9c68f838af856cc3331a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>ATAC-seq</topic><topic>autism</topic><topic>Autistic Disorder - genetics</topic><topic>Cell Line</topic><topic>chromatin</topic><topic>Chromatin - genetics</topic><topic>Chromatin - metabolism</topic><topic>Chromatin Immunoprecipitation Sequencing</topic><topic>Enhancer Elements, Genetic</topic><topic>enhancers</topic><topic>Euchromatin - genetics</topic><topic>GABA Plasma Membrane Transport Proteins - genetics</topic><topic>Gene Expression Regulation, Developmental - genetics</topic><topic>Gene Ontology</topic><topic>gene regulation</topic><topic>Genetic Predisposition to Disease</topic><topic>Gestational Age</topic><topic>Humans</topic><topic>machine learning</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>neurodevelopment</topic><topic>neuropsychiatric disorders</topic><topic>Nucleotide Motifs</topic><topic>Point Mutation</topic><topic>Prefrontal Cortex - embryology</topic><topic>Prefrontal Cortex - metabolism</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Spatio-Temporal Analysis</topic><topic>Telencephalon - embryology</topic><topic>Telencephalon - metabolism</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Markenscoff-Papadimitriou, Eirene</creatorcontrib><creatorcontrib>Whalen, Sean</creatorcontrib><creatorcontrib>Przytycki, Pawel</creatorcontrib><creatorcontrib>Thomas, Reuben</creatorcontrib><creatorcontrib>Binyameen, Fadya</creatorcontrib><creatorcontrib>Nowakowski, Tomasz J.</creatorcontrib><creatorcontrib>Kriegstein, Arnold R.</creatorcontrib><creatorcontrib>Sanders, Stephan J.</creatorcontrib><creatorcontrib>State, Matthew W.</creatorcontrib><creatorcontrib>Pollard, Katherine S.</creatorcontrib><creatorcontrib>Rubenstein, John L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Markenscoff-Papadimitriou, Eirene</au><au>Whalen, Sean</au><au>Przytycki, Pawel</au><au>Thomas, Reuben</au><au>Binyameen, Fadya</au><au>Nowakowski, Tomasz J.</au><au>Kriegstein, Arnold R.</au><au>Sanders, Stephan J.</au><au>State, Matthew W.</au><au>Pollard, Katherine S.</au><au>Rubenstein, John L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Chromatin Accessibility Atlas of the Developing Human Telencephalon</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2020-08-06</date><risdate>2020</risdate><volume>182</volume><issue>3</issue><spage>754</spage><epage>769.e18</epage><pages>754-769.e18</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Conceptualization, EMP, SW, KSP, JLR; Investigation, EMP, SW; Methodology, EMP, SW, PP, RT, KSP; Validation, EMP, FB; Software, SW, PP, RT; Formal Analysis, EMP, SW, PP, RT; Resources, TN, SS, JLR, KSP, ARK; Data Curation, SW, SS; Writing, Original Draft Preparation, EMP, SW, PP, KSP, JLR.; Writing, Review & Editing, EMP, SW, PP, SS, MWS, KSP, JLR; Visualization, EMP, SW, PP; Supervision, SS, MWS, KSP, JLR; Project Administration, EMP, SW, KSP, JLR; Funding Acquisition, MWS, KSP, JLR.</notes><notes>Lead author</notes><notes>Author Contributions</notes><notes>Contributed equally</notes><abstract>To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.
[Display omitted]
•∼19,000 enhancers defined in nine regions of the developing human telencephalon•Chromatin dynamics correlate with sequence motifs and spatiotemporal gene expression•Identified cortical layer-specific enhancers and validated a layer 5 FEZF2 enhancer•Genetic variants from patients alter activity of an enhancer for an autism risk gene
A high-resolution atlas of regulatory elements driving regional, temporal, and laminar gene expression programs in the developing human telencephalon reveals enhancers and genetic variants regulating human disease genes.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32610082</pmid><doi>10.1016/j.cell.2020.06.002</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals ATAC-seq autism Autistic Disorder - genetics Cell Line chromatin Chromatin - genetics Chromatin - metabolism Chromatin Immunoprecipitation Sequencing Enhancer Elements, Genetic enhancers Euchromatin - genetics GABA Plasma Membrane Transport Proteins - genetics Gene Expression Regulation, Developmental - genetics Gene Ontology gene regulation Genetic Predisposition to Disease Gestational Age Humans machine learning Mice Mice, Transgenic neurodevelopment neuropsychiatric disorders Nucleotide Motifs Point Mutation Prefrontal Cortex - embryology Prefrontal Cortex - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Spatio-Temporal Analysis Telencephalon - embryology Telencephalon - metabolism Transcription Factors - genetics Transcription Factors - metabolism |
| title | A Chromatin Accessibility Atlas of the Developing Human Telencephalon |
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