Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states Journal Article

  

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Authors:	Southard, K. M.; Ardy, R. C.; Tang, A.; O'Sullivan, D. D.; Metzner, E.; Guruvayurappan, K.; Norman, T. M.
Article Title:	Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states
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.
Keywords:	fibrosis; model; sites; atlas; seq; cell states
Journal Title:	Nature Genetics
Volume:	57
Issue:	9
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Publication status:	Published
Date Published:	2025-09-01
Start Page:	2323
End Page:	2334
Language:	English
ACCESSION:	WOS:001545352500001
DOI:	10.1038/s41588-025-02284-1
PROVIDER:	wos
PUBMED:	40770575
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Thomas M. Norman -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/228821