单细胞RNA测序揭示多巴胺能神经元的分化进程

作者：张馨予

本期文章：《自然—遗传学》：Online/在线发表

英国惠康基金会基因组校园Oliver Stegle、Daniel J. Gaffney、John C. Marioni和剑桥大学Florian T. Merkle研究组合作取得一项新成果。经过不懈努力，他们揭示了多巴胺能神经元分化群体尺度的单细胞RNA-seq分析。相关论文于2021年3月4日发表于国际学术期刊《自然-遗传学》杂志。

为了研究常见遗传变异的功能，研究人员使用有效的多重策略诱导215个人多能干细胞（iPSC）定向分化为中脑神经细胞（包括多巴胺能神经元），并使用单细胞RNA测序（scRNA-seq）在三个分化时间点分析了超过一百万个细胞。每个细胞系产生的神经元比例是高度可重复的，并且可以通过在多能干细胞中表达的有效分子标记来预测。

定量性状基因座（eQTL）在神经元发育的不同阶段表达并通过响应鱼藤酮诱导的氧化应激进行表征。其中1,284个eQTL与已知的神经系统性状危险基因座共定位，其中46％是在基因型-组织表达（GTEx）检测中未发现的。该研究表明，将scRNA-seq与iPSC的长期分化相结合可以对在其他情况下无法检测的细胞状态与人类性状相关的遗传变异进行机理研究。

据悉，在人体组织和发育过程中研究常见遗传变异的功能具有一定挑战性。

附：英文原文

Title: Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation

Author: Julie Jerber, Daniel D. Seaton, Anna S. E. Cuomo, Natsuhiko Kumasaka, James Haldane, Juliette Steer, Minal Patel, Daniel Pearce, Malin Andersson, Marc Jan Bonder, Ed Mountjoy, Maya Ghoussaini, Madeline A. Lancaster, John C. Marioni, Florian T. Merkle, Daniel J. Gaffney, Oliver Stegle

Issue&Volume: 2021-03-04

Abstract: Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype–Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.

DOI: 10.1038/s41588-021-00801-6

Source: https://www.nature.com/articles/s41588-021-00801-6

期刊信息

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：25.455
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex