Transcriptome and epigenome landscape of human cortical development modeled in organoids
Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysi...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2018-12, Vol.362 (6420) |
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| creator | Amiri, Anahita Coppola, Gianfilippo Scuderi, Soraya Wu, Feinan Roychowdhury, Tanmoy Liu, Fuchen Pochareddy, Sirisha Shin, Yurae Safi, Alexias Song, Lingyun Zhu, Ying Sousa, André M M Gerstein, Mark Crawford, Gregory E Sestan, Nenad Abyzov, Alexej Vaccarino, Flora M |
| description | Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset. |
| doi_str_mv | 10.1126/science.aat6720 |
| format | Article |
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We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aat6720</identifier><identifier>PMID: 30545853</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Annotations ; Autism ; Autism Spectrum Disorders ; Binding sites ; Biological evolution ; Brain ; Cerebral cortex ; Cerebral Cortex - embryology ; Children ; Convergence ; Developmental stages ; Disabilities ; Disorders ; Embryogenesis ; Embryos ; Enhancer Elements, Genetic ; Enhancers ; Enrichment ; Epidemiology ; Epigenesis, Genetic ; Etiology ; Fetuses ; Gene expression ; Gene Expression Regulation, Developmental ; Gene regulation ; Genes ; Genomes ; Glial cells ; Homeobox ; Humans ; Induced Pluripotent Stem Cells - cytology ; Intellectual disabilities ; Mental disorders ; Models, Neurological ; Modules ; Mutation ; Network analysis ; Neurogenesis - genetics ; Organoids ; Organoids - embryology ; Pluripotency ; Radial glial cells ; Regulatory sequences ; Schizophrenia ; Stem cells ; Temporal cortex ; Transcription factors ; Transcriptome ; Transportation networks ; Weight</subject><ispartof>Science (American Association for the Advancement of Science), 2018-12, Vol.362 (6420)</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.</description><subject>Annotations</subject><subject>Autism</subject><subject>Autism Spectrum Disorders</subject><subject>Binding sites</subject><subject>Biological evolution</subject><subject>Brain</subject><subject>Cerebral cortex</subject><subject>Cerebral Cortex - embryology</subject><subject>Children</subject><subject>Convergence</subject><subject>Developmental stages</subject><subject>Disabilities</subject><subject>Disorders</subject><subject>Embryogenesis</subject><subject>Embryos</subject><subject>Enhancer Elements, Genetic</subject><subject>Enhancers</subject><subject>Enrichment</subject><subject>Epidemiology</subject><subject>Epigenesis, Genetic</subject><subject>Etiology</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genomes</subject><subject>Glial cells</subject><subject>Homeobox</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - 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| subjects | Annotations Autism Autism Spectrum Disorders Binding sites Biological evolution Brain Cerebral cortex Cerebral Cortex - embryology Children Convergence Developmental stages Disabilities Disorders Embryogenesis Embryos Enhancer Elements, Genetic Enhancers Enrichment Epidemiology Epigenesis, Genetic Etiology Fetuses Gene expression Gene Expression Regulation, Developmental Gene regulation Genes Genomes Glial cells Homeobox Humans Induced Pluripotent Stem Cells - cytology Intellectual disabilities Mental disorders Models, Neurological Modules Mutation Network analysis Neurogenesis - genetics Organoids Organoids - embryology Pluripotency Radial glial cells Regulatory sequences Schizophrenia Stem cells Temporal cortex Transcription factors Transcriptome Transportation networks Weight |
| title | Transcriptome and epigenome landscape of human cortical development modeled in organoids |
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