{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T18:56:51Z","timestamp":1760986611017,"version":"build-2065373602"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":50,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Municipal Science and Technology Major Project","award":["ZD2021CY001"],"award-info":[{"award-number":["ZD2021CY001"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272376","32470186"],"award-info":[{"award-number":["82272376","32470186"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Differential expression (DE) analysis based on transcriptomic data provides a genome-wide assessment of gene responsiveness. We recently characterized transcriptional plasticity (TP)\u2014the variability of gene expression in response to environmental changes\u2014but its impact on DE analysis remained unexplored. In this work, we examined how TP affects DE analysis and introduced a TP-aware framework to improve the interpretation of DE results. We revealed correlations between fold change of gene expression and TP in 238 experiments with Mycobacterium tuberculosis (Mtb) and Escherichia coli (E. coli), which carried inherent biases, favoring genes with high TP while overlooking those with low TP. Therefore, we employed Locally Estimated Scatterplot Smoothing on TP to adjust the fold change of gene expression. Adjusted DE analyses identified new responsive pathways and yielded higher overall statistical significance and enrichment scores, especially for pathways with low-TP genes. Specifically, adjusted DE results revealed that bedaquiline treatment of Mtb induced cholesterol degradation, linezolid repressed acetate metabolism, and infection of macrophages upregulated fatty acid metabolism while downregulating cofactor biosynthesis. We also demonstrate that the adjustment strategy can be applied to other bacterial species and is compatible with various RNA-seq quantification approaches. In summary, we introduce a TP-aware approach that normalizes DE analysis by correcting for inherent transcriptional variability.<\/jats:p>","DOI":"10.1093\/bib\/bbaf557","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T17:14:16Z","timestamp":1760980456000},"source":"Crossref","is-referenced-by-count":0,"title":["A transcriptional plasticity-aware framework for RNA-seq differential expression analysis"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3315-5837","authenticated-orcid":false,"given":"Cheng","family":"Bei","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), School of Basic Medical Science, Shanghai Medical College, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University , 138 Yixueyuan Rd, Xuhui District, Shanghai 200032 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoman","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences , No. 1 Beichen West Road, Chaoyang District, Beijing 100101 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyu","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill , 120 Mason Farm Rd, Chapel Hill, NC 27599 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard E","family":"Takiff","sequence":"additional","affiliation":[{"name":"Instituto Venezolano de Investigaciones Cientificas (IVIC) , Carr. 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