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Here, we present TFActProfiler, a TF\u2013mRNA resource and computational framework that learns signed, quantitative TF\u2013mRNA regulatory coefficients by integrating heterogeneous prior evidence (ChIP-based, motif-based, and curated TF\u2013mRNA annotations) with large-scale bulk and single-cell RNA-seq atlases. TFActProfiler contains 2\u2009606\u2009176 signed TF\u2013mRNA interactions and improves TF activity inference in TF knockdown benchmarks relative to widely used regulon resources while retaining broad TF and target coverage. In addition, because the same learned regulatory coefficients can be used to model downstream transcriptional effects, TFActProfiler enables prediction of transcriptome-wide gene expression responses to TF knockdown without training on task-matched perturbation data. When perturbation datasets are available, TFActProfiler can be further refined to achieve performance comparable to state-of-the-art machine-learning baselines. By providing a direction-aware representation of TF\u2013mRNA regulation for both activity inference and perturbation-response modeling, TFActProfiler supports systematic dissection of gene regulatory programs across diverse cellular contexts.<\/jats:p>","DOI":"10.1093\/nar\/gkag897","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:33:11Z","timestamp":1788521591000},"source":"Crossref","is-referenced-by-count":0,"title":["A transcription factor regulatory atlas for activity inference and perturbation prediction"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6468-0127","authenticated-orcid":false,"given":"Hikaru","family":"Sugimoto","sequence":"first","affiliation":[{"name":"Department of Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University , 1-8-1 Inohana, Chuo, Chiba, Chiba 260-8670 ,","place":["Japan"]},{"name":"Predictive Medicine Special Project (PMSP), RIKEN Center for Integrative Medical Sciences (IMS), RIKEN , Yokohama, Kanagawa 230-0045 ,","place":["Japan"]},{"name":"Division of Applied Mathematical Science, RIKEN Center for Interdisciplinary Theoretical and Mathematical Sciences (iTHEMS), RIKEN , Wako, Saitama 351-0198 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3797-2148","authenticated-orcid":false,"given":"Koki","family":"Tsuyuzaki","sequence":"additional","affiliation":[{"name":"Data Science Core, Chiba University , 1-8-1 Inohana, Chuo, Chiba, Chiba 260-8670 ,","place":["Japan"]},{"name":"Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research , Wako, Saitama 351-0198 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1075-4936","authenticated-orcid":false,"given":"Zhaonan","family":"Zou","sequence":"additional","affiliation":[{"name":"Institute of Resource Development and 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