小柯机器人

美国哈佛医学院Steven A. McCarroll等研究人员合作利用神经祖细胞村揭示基因表达和病毒易感性的自然变异。2023年2月15日，《细胞—干细胞》杂志在线发表了这项成果。

研究人员描述了一个“细胞村”实验平台，被用于分析来自44个人类供体的神经祖细胞的遗传、分子和表型异质性，这些细胞在一个共享的体外环境中培养，并通过算法（Dropulation和Census-seq）来将细胞和表型分配给单个供体。通过快速诱导人类干细胞来源的神经祖细胞、测量自然遗传变异和CRISPR-Cas9遗传扰动，研究人员发现了一种常见的变体，它调节抗病毒药物IFITM3的表达，并解释了大多数个体间对寨卡病毒敏感性的差异。研究人员人员还检测了与脑特征GWAS位点相对应的表达QTL，并发现了新的与祖细胞增殖和分化相关的疾病调控因子，如CACHD1。这种方法提供了可扩展的方法来阐明基因和遗传变异对细胞表型的影响。

据了解，人类基因组变异有助于神经发育结果和脆弱性的多样性；鉴别到潜在的分子和细胞机制将需要可扩展的方法。

附：英文原文

Title: Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages

Author: Michael F. Wells, James Nemesh, Sulagna Ghosh, Jana M. Mitchell, Max R. Salick, Curtis J. Mello, Daniel Meyer, Olli Pietilainen, Federica Piccioni, Ellen J. Guss, Kavya Raghunathan, Matthew Tegtmeyer, Derek Hawes, Anna Neumann, Kathleen A. Worringer, Daniel Ho, Sravya Kommineni, Karrie Chan, Brant K. Peterson, Joseph J. Raymond, John T. Gold, Marco T. Siekmann, Emanuela Zuccaro, Ralda Nehme, Ajamete Kaykas, Kevin Eggan, Steven A. McCarroll

Issue&Volume: 2023-02-15

Abstract: Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular and cellular mechanisms will require scalable approaches. Here, we describe a “cell village” experimental platform we used to analyze genetic, molecular, and phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors. Through rapid induction of human stem cell-derived neural progenitor cells, measurements of natural genetic variation, and CRISPR-Cas9 genetic perturbations, we identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus. We also detected expression QTLs corresponding to GWAS loci for brain traits and discovered novel disease-relevant regulators of progenitor proliferation and differentiation such as CACHD1. This approach provides scalable ways to elucidate the effects of genes and genetic variation on cellular phenotypes.

DOI: 10.1016/j.stem.2023.01.010

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00035-8

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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