SPARCS实现用于遗传筛选的复杂图像表型的可扩展恢复
SPARCS实现用于遗传筛选的复杂图像表型的可扩展恢复
作者： 小柯机器人 发布时间：2026/10/7 13:07:24
本期文章：《细胞》：Online/在线发表
德国慕尼黑路德维希-马克西米利安大学Veit Hornung团队取得一项新突破。他们的最新研究探明了SPARCS使复杂的基于图像的表型遗传筛选的可扩展恢复。这一研究成果发表在2026年10月6日出版的国际学术期刊《细胞》上。
正向遗传筛选通过引入随机遗传扰动并鉴定改变表型的突变，将基因型与表型联系起来。尽管基因组规模筛选对于培养细胞中的简单表型已是常规操作，但将其扩展到复杂的基于图像的表型仍具挑战性。在此，研究人员提出了空间分辨CRISPR筛选（SPARCS），一种基于显微镜的单细胞图像正向遗传筛选平台。SPARCS通过自动激光显微切割原位物理分离突变体，使得能够以前所未有的规模进行基于图像的筛选，并进行多模态命中表型分析。研究人员在跨越7000万个细胞的自噬体形成和免疫传感器STING激活的全基因组CRISPR敲除筛选中展示了SPARCS。通过基于机器学习的图像分析，SPARCS恢复了大多数巨自噬基因，并鉴定出GPHR是STING的pH依赖性调控因子。对分离出的命中细胞的基于质谱的蛋白质组学分析揭示了内质网/高尔基体破坏，并通过计算机扰动建模提名了额外的STING调控因子。这些结果确立了SPARCS作为一个可扩展的平台，用于对复杂细胞表型进行全基因组遗传筛选，并具有蛋白质组水平的读出。
附：英文原文
Title: SPARCS enables scalable recovery of complex image-based phenotypes for genetic screening
Author: Niklas A. Schmacke, Sophia C. Mdler, Georg Wallmann, Andreas Metousis, Varvara Varlamova, Sophia Steigerwald, Sarah B. Christ, Marleen Bérouti, Hartmann Harz, Heinrich Leonhardt, Fabian J. Theis, Matthias Mann, Veit Hornung
Issue&Volume: 2026-10-06
Abstract: Forward genetic screening links genotype to phenotype by introducing random genetic perturbations and identifying phenotype-altering mutations. Although genome-scale screens are routine for simple phenotypes in cultured cells, extending them to complex image-based phenotypes remains challenging. Here, we present spatially resolved CRISPR screening (SPARCS), a microscopy-based platform for forward genetic screening on single-cell images. SPARCS physically isolates mutants in situ by automated laser microdissection, enabling image-based screening at unprecedented scale with multimodal hit phenotyping. We demonstrate SPARCS in genome-wide CRISPR knockout screens of autophagosome formation and activation of the immune sensor STING across 70 million cells. Via machine learning-based image analysis, SPARCS recovered most macroautophagy genes and identified GPHR as a pH-dependent regulator of STING. Mass spectrometry-based proteomics of isolated hit cells revealed endoplasmic reticulum (ER)/Golgi disruption and nominated additional STING regulators via in silico perturbation modeling. These results establish SPARCS as a scalable platform for genome-wide genetic screening of complex cellular phenotypes with a proteome-level readout.
DOI: 10.1016/j.cell.2026.09.021
Source: https://www.cell.com/cell/abstract/S0092-8674(26)01123-2
主题：基于图像