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Transcriptome and epigenome landscape of human cortical development modeled in organoids

2018; American Association for the Advancement of Science; Volume: 362; Issue: 6420 Linguagem: Inglês

10.1126/science.aat6720

1095-9203

Anahita Amiri, Gianfilippo Coppola, Soraya Scuderi, Feinan Wu, Tanmoy Roychowdhury, Fuchen Liu, Sirisha Pochareddy, Yurae Shin, Alexias Safi, Lingyun Song, Ying Zhu, André M. M. Sousa, Mark Gerstein, Gregory E. Crawford, Nenad Šestan, Alexej Abyzov, Flora M. Vaccarino, Schahram Akbarian, Joon‐Yong An, Christoper Armoskus, Allison E. Ashley‐Koch, Thomas G. Beach, Judson Belmont, Jaroslav Bendl, Tyler Borrman, Leanne Brown, Miguel Brown, Mimi Brown, Tonya M. Brunetti, Julien Bryois, Emily E. Burke, Adrian Camarena, Becky C. Carlyle, Yooree Chae, Alexander W. Charney, Chao Chen, Lijun Cheng, Adriana Cherskov, Jinmyung Choi, Declan Clarke, Leonardo Collado‐Torres, Rujia Dai, Luis de la Torre-Ubieta, Diane M. Del Valle, Olivia Devillers, Stella Dracheva, Prashant S. Emani, Oleg V. Evgrafov, Peggy Farnham, Dominic Fitzgerald, Elie Flatow, Nancy Francoeur, John F. Fullard, Michael J. Gandal, Tianliuyun Gao, Melanie E. Garrett, Daniel H. Geschwind, Gina Giase, Kiran Girdhar, Paola Giusti‐Rodríguez, Fernando S. Goes, Thomas Goodman, Kay Grennan, Mengting Gu, Gamze Gürsoy, Evi Hadjimichael, Chang-Gyu Hahn, Vahram Haroutunian, Mads E. Hauberg, Gabriel E. Hoffman, Jack Huey, Thomas M. Hyde, Nikolay A. Ivanov, Rivka Jacobov, Andrew E. Jaffe, Yan Jiang, Yi Jiang, Graham D. Johnson, Bibi Kassim, Amira Kefi, Yunjung Kim, Robert R. Kitchen, Joel E. Kleiman, James A. Knowles, Alexey Kozlenkov, Mingfeng Li, Zhen Li, Barbara K. Lipska, Chunyu Liu, Shuang Liu, Lara M. Mangravite, Jessica Mariani, Eugenio Mattei, Daniel J. Miller, J. Russell Moore, Angus C. Nairn, Fábio C. P. Navarro, Royce Park, Mette A. Peters, Dalila Pinto, Sirisha Pochareddy, Damon Polioudakis, Henry Pratt, Amanda J. Price, Michael Purcaro, Mohana Ray, Timothy E. Reddy, Suhn K. Rhie, Panos Roussos, Stephan Sanders, Gabriel Santpere, Shannon Schreiner, Brooke Sheppard, Xu Shi, Annie W. Shieh, Joo Heon Shin, Mario Škarica, Lingyun Song, André M. M. Sousa, Valeria N. Spitsyna, Matthew W. State, Patrick F. Sullivan, Vivek Swarup, Jin Szatkiewicz, Anna Szekely, Ran Tao, Harm van Bakel, Yongjun Wang, Daifeng Wang, Jonathan Warrell, Maree J. Webster, Sherman M. Weissman, Zhiping Weng, Donna M. Werling, Kevin P. White, Jeremy A. Willsey, Jennifer Wiseman, Heather Witt, Hyejung Won, Gregory A. Wray, Yan Xia, Min Xu, Yucheng Yang, Mo Yang, Peter P. Zandi, Jing Zhang, Elizabeth Zharovsky,

Epigenetics and DNA Methylation

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.