Massively parallel characterization of regulatory elements in the developing human cortex

• 成果类型: Article
• 署名作者: Deng, Chengyu; Whalen, Sean; Steyert, Marilyn; Ziffra, Ryan; Przytycki, Pawel F.; Inoue, Fumitaka; Pereira, Daniela A.; Capauto, Davide; Norton, Scott; Vaccarino, Flora M.; Pollen, Alex A.; Nowakowski, Tomasz J.; Ahituv, Nadav; Pollard, Katherine S.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Chan Zuckerberg Initiative (CZI); University of California System; University of California San Francisco; University of California System; University of California San Francisco; Kyoto University; Universidade Federal de Minas Gerais; Yale University; Yale University; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13245
• DOI: 10.1126/science.adh0559
• 发表日期: 2024-05-24
• 关键词: reveals mechanisms; disorders; organoids; identification; specification; mutations; variants; database; models; genes

摘要

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.