Massively parallel characterization of regulatory elements in the developing human cortex
Chengyu Deng(University of California, San Francisco), Sean Whalen(Gladstone Institutes), Marilyn Steyert(University of California, San Francisco), Ryan Ziffra(University of California, San Francisco), Pawel F. Przytycki(Gladstone Institutes), Fumitaka Inoue(Kyoto University), Daniela A. Pereira(Universidade Federal de Minas Gerais), Davide Capauto(Yale University), Scott Norton(Yale University), Flora M. Vaccarino(Yale University), Alex A. Pollen(University of California, San Francisco), Tomasz J. Nowakowski(University of California, San Francisco), Nadav Ahituv(University of California, San Francisco), Katherine S. Pollard(Gladstone Institutes), Schahram Akbarian, Alexej Abyzov, Nadav Ahituv(University of California, San Francisco), Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul Bharadwaj, Arjun Bhattacharya, Lucy Bicks, Kristen Brennand, Davide Capauto(Yale University), Frances A. Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen(University of California, San Francisco), H. Isaac Chen(University of California, San Francisco), Yuyan Cheng(University of California, San Francisco), Lijun Cheng(University of California, San Francisco), Andrew Chess, Jo-fan Chien, Zhiyuan Chu, Declan Clarke, Ashley Clement, Leonardo Collado‐Torres, Gregory M. Cooper, Gregory E. Crawford, Rujia Dai, Nikolaos P. Daskalakis, José Dávila-Velderrain, Amy Deep‐Soboslay, Chengyu Deng(University of California, San Francisco), Christopher P. DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc M. Duong, Cagatay Dursun, Nicholas J. Eagles, Jonathan I. Edelstein, Prashant S. Emani, John F. Fullard, Kiki Galani, Timur R. Galeev, Michael J. Gandal, Sophia C. Gaynor, Mark Gerstein, Daniel H. Geschwind, Kiran Girdhar, Fernando S. Goes, William J. Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He(Gladstone Institutes), Ella Henry, Stephanie C. Hicks, Marcus Ho, Li‐Lun Ho, Gabriel E. Hoffman, Yi‐Ling Huang, Louise A. Huuki-Myers, Ahyeon Hwang, Thomas M. Hyde, Artemis Iatrou, Fumitaka Inoue(Kyoto University), Aarti Jajoo, Matthew L. Jensen, Lihua Jiang, Jin Peng, Ting Jin, Connor Jops, Alexandre Jourdon, Riki Kawaguchi, Manolis Kellis, Saniya Khullar, Joel E. Kleinman, Steven P. Kleopoulos, Alexey Kozlenkov(University of California, San Francisco), Arnold R. Kriegstein, Anshul Kundaje, Soumya Kundu, Che-Yu Lee, Donghoon Lee, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Jason Liu, Jianyin Liu, Chunyu Liu, Shuang Liu, Shaoke Lou, Jacob M. Loupe, Dan Lü(Universidade Federal de Minas Gerais), Shaojie Ma(University of California, San Francisco), Liang Ma(University of California, San Francisco), Michael Margolis, Jessica Mariani, Keri Martinowich, Kristen R. Maynard, Samantha Mazariegos, Ran Meng, Richard M. Myers, Courtney Micallef, Tatiana Mikhailova, Guo‐li Ming, Shahin Mohammadi, Emma Monte, Kelsey S. Montgomery, Jill E. Moore, Jennifer Moran, Eran A. Mukamel, Angus C. Nairn, Charles B. Nemeroff, Pengyu Ni(Universidade Federal de Minas Gerais), Scott Norton(Yale University), Tomasz J. Nowakowski(University of California, San Francisco), Larsson Omberg, Stephanie C. Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Mette A. Peters, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Katherine S. Pollard(Gladstone Institutes), Alex A. Pollen(University of California, San Francisco), Henry Pratt, Pawel F. Przytycki(Gladstone Institutes), Carolin Purmann, Zhaohui Qin, Pingping Qu, Diana Quintero, Towfique Raj, Ananya S. Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J. Ressler, D D Ross, Panos Roussos, Joel Rozowsky, Misir Ruth, W. Brad Ruzicka, Stephan Sanders, Juliane M. Schneider, Soraya Scuderi, Robert Sebra, Nenad Šestan, Nicholas T. Seyfried, Zhiping Shao, Nicole Shedd, Annie W. Shieh, Joo Heon Shin, Mario Škarica, Clara Snijders, Hongjun Song, Matthew W. State, Jason L. Stein, Marilyn Steyert(University of California, San Francisco), Sivan Subburaju, Thomas C. Südhof, M Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander E. Urban, Flora M. Vaccarino(Yale University), Harm van Bakel, Daniel Vo(Universidade Federal de Minas Gerais), Georgios Voloudakis, Brie Wamsley, Tao Wang, Sidney H. Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Wei Yu(University of California, San Francisco), Annika K. Weimer, Daniel R. Weinberger, Cindy Wen, Zhiping Weng, Sean Whalen(Gladstone Institutes), Kevin P. White, A. Jeremy Willsey, Hyejung Won, Wing H. Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X. Yap, Biao Zeng, Pan Zhang, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra(University of California, San Francisco), Zane Zeier, Trisha M. Zintel
Cited by 61Open Access
Abstract
Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.
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