Journal Article

Transcriptome and epigenome landscape of human cortical development modeled in organoids

Hadjimichael, Evi, Polioudakis, Damon, Xu, Min, Wu, Feinan, Pochareddy, Sirisha, Fitzgerald, Dominic, Li, Mingfeng, Zhang, Jing, Won, Hyejung, Armoskus, Christoper, Moore, Jill, Borrman, Tyler, Warrell, Jonathan, Miller, Daniel J., Navarro, Fabio C. P., Kitchen, Robert R., Sanders, Stephan J., Giusti-Rodriguez, Paola, DelValle, Diane, Hoffman, Gabriel E., Zandi, Peter, State, Matthew W., Brown, Miguel, Weng, Zhiping, Chae, Yooree, Xia, Yan, Ray, Mohana, Francoeur, Nancy, Abyzov, Alexej, Hahn, Chang-Gyu, Evgrafov, Oleg V., Szekely, Anna, Gürsoy, Gamze, Geschwind, Daniel H., Zharovsky, Elizabeth, Sheppard, Brooke, White, Kevin P., Devillers, Olivia, Hauberg, Mads E., Clarke, Declan, Amiri, Anahita, Akbarian, Schahram, Mariani, Jessica, van Bakel, Harm, Wang, Daifeng, Wiseman, Jennifer R., Goodman, Thomas, Mattei, Eugenio, Gao, Tianliuyun, Pratt, Henry, Giase, Gina, Shin, Joo Heon, Dai, Rujia, Yang, Yucheng T., Liu, Chunyu, Yang, Mo, Coppola, Gianfilippo, Cherskov, Adriana, Price, Amanda J., Song, Lingyun, Carlyle, Becky C., Willsey, Jeremy A., Liu, Shuang, Sousa, André M. M., Ivanov, Nikolay A., Li, Zhen, Webster, Ma

2018

Overview

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.

• Publisher: The American Association for the Advancement of Science
• Subject: Annotations / Autism / Autism Spectrum Disorders / Binding sites / Biological evolution / Brain / Cerebral cortex / Cerebral Cortex - embryology / Children / Convergence / Developmental stages / 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 lobe / Transcription factors / Transcriptome / Transportation networks / Weight