Massively parallel characterization of regulatory elements in the developing human cortex

作者：Chengyu Deng, Chengyu Deng, Sean Whalen, Sean Whalen, Marilyn Steyert, Ryan Ziffra, Pawel F. Przytycki, Fumitaka Inoue, Daniela A. Pereira, Davide Capauto, Scott Norton, Flora M. Vaccarino, Alex A. Pollen, Tomasz J. Nowakowski, Nadav Ahituv, Katherine S. Pollard, Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul Bharadwaj, Arjun Bhattacharya, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A. Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuyan Cheng, Lijun Cheng, Yuyan Cheng, Lijun Cheng, 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, Chengyu Deng, 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, 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, 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, Alex Kozlenkov, Arnold R. Kriegstein, Anshul Kundaje, Soumya Kundu, Cheyu Lee, Donghoon Lee, Shuang Liu, Mingfeng Li, Xiao Lin, Chunyu Liu, Jason Liu, Shaoke Lou, Chunyu Liu, Dan Lü, Shaoke Lou, Jacob M. Loupe, Dan Lü, Shaojie Ma, Liang Ma, 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, Scott Norton, Tomasz Nowakowski, 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, Alex Pollen, Henry Pratt, Pawel F. Przytycki, 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, Sivan Subburaju, Thomas C. Südhof, M Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander E. Urban, Flora M. Vaccarino, Harm van Bakel, Daniel Vo, Georgios Voloudakis, Brie Wamsley, Yifan Wang, Sidney H. Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Cindy Wen, Annika K. Weimer, Daniel R. Weinberger, Cindy Wen, Zhiping Weng, Sean Whalen, Sean Whalen, Kevin P. White, A. Jeremy Willsey, Hyejung Won, Wing H. Wong, Siwei Xu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X. Yap, Biao Zeng, Yanqiong Zhang, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra, Zane Zeier, Trisha M. Zintel · 发表于：Science · 年份：2024 · DOI：10.1126/science.adh0559 · 被引用次数：67 · 研究领域：Genomics and Chromatin Dynamics、RNA Research and Splicing、RNA and protein synthesis mechanisms

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.