综合转录因子扰动再现成纤维细胞的转录状态，这一成果由纪念斯隆-凯特琳癌症中心Thomas M. Norman课题组经过不懈努力而取得。2025年8月6日出版的《自然—遗传学》杂志发表了这一最新研究成果。

研究团队发现转录因子的系统激活可以在体外重建这种状态，为机制和功能研究提供了可处理的模型。使用可扩展的CRISPR激活（CRISPRa） Perturb-seq平台，研究小组激活了两种细胞类型中的1836个转录因子。CRISPRa在生理范围内诱导基因表达，染色质特征预测反应性。与图谱数据集的比较显示，转录因子扰动再现了关键的成纤维细胞状态，并确定了它们的调节因子，包括KLF2和KLF4，这是许多组织中普遍存在的状态，PLAGL1是疾病相关的炎症状态。诱导普遍状态抑制炎症状态，提示治疗潜力。这些发现将CRISPRa定位为干扰分化细胞的微妙工具，并建立了研究体外临床相关转录状态的一般策略。

据介绍，细胞图谱项目揭示了常见的细胞类型通常包含不同的、反复的转录状态，但这些状态的功能和调控仍然知之甚少。

附：英文原文

Title: Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states

Author: Southard, Kaden M., Ardy, Rico C., Tang, Anran, OSullivan, Deirdre D., Metzner, Eli, Guruvayurappan, Karthik, Norman, Thomas M.

Issue&Volume: 2025-08-06

Abstract: Cell atlas projects have revealed that common cell types often comprise distinct, recurrent transcriptional states, but the function and regulation of these states remain poorly understood. Here, we show that systematic activation of transcription factors can recreate such states in vitro, providing tractable models for mechanistic and functional studies. Using a scalable CRISPR activation (CRISPRa) Perturb-seq platform, we activated 1,836 transcription factors in two cell types. CRISPRa induced gene expression within physiological ranges, with chromatin features predicting responsiveness. Comparisons with atlas datasets showed that transcription factor perturbations recapitulated key fibroblast states and identified their regulators, including KLF2 and KLF4 for a universal state present in many tissues, and PLAGL1 for a disease-associated inflammatory state. Inducing the universal state suppressed the inflammatory state, suggesting therapeutic potential. These findings position CRISPRa as a nuanced tool for perturbing differentiated cells and establish a general strategy for studying clinically relevant transcriptional states ex vivo.

DOI: 10.1038/s41588-025-02284-1

Source: https://www.nature.com/articles/s41588-025-02284-1