研究人员在妊娠中期皮层和脑类器官的原代人体细胞中使用大规模平行报告分析法，对102767个开放染色质区域的顺式调控活性进行了研究，其中包括数千个具有细胞类型特异性的序列和与脑基因调控相关的变体。在原代细胞中，研究人员发现了46802个活性增强子序列和164个改变增强子活性的变体。
类器官和原代细胞中的活性相当，这表明类器官为发育中的大脑皮层提供了一个适当的模型。通过深度学习，研究人员解码了增强子活性的序列基础和上游调控因子。这项工作为人类神经元发育过程中的功能基因调控元件和变体建立了一个全面的目录。
据了解，基因调控元件的核苷酸变化是神经元发育和疾病的重要决定因素。
附：英文原文
Title: Massively parallel characterization of regulatory elements in the developing human cortex
Author: Chengyu Deng, Sean Whalen, Marilyn Steyert, Ryan Ziffra, Pawel F. Przytycki, Fumitaka Inoue, Daniela A. Pereira, Davide Capauto, Scott Norton, Flora M. Vaccarino, PsychENCODE Consortium, Alex A. Pollen, Tomasz J. Nowakowski, Nadav Ahituv, Katherine S. Pollard
Issue&Volume: 2024-05-24
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.
DOI: adh0559
Source: https://www.science.org/doi/10.1126/science.adh0559