title: Modulation of gene expression regulated by the transcription factor NF-κB/RelA.
abstract: Modulators (Ms) are proteins that modify the activity of transcription factors (TFs) and influence expression of their target genes (TGs). To discover modulators of NF-κB/RelA, we first identified 365 NF-κB/RelA-binding proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used a probabilistic model to infer 8349 (M, NF-κB/RelA, TG) triplets and their modes of modulatory action from our combined LC-MS/MS and ChIP-Seq (ChIP followed by next generation sequencing) data, published RelA modulators and TGs, and a compendium of gene expression profiles. Hierarchical clustering of the derived modulatory network revealed functional subnetworks and suggested new pathways modulating RelA transcriptional activity. The modulators with the highest number of TGs and most non-random distribution of action modes (measured by Shannon entropy) are consistent with published reports. Our results provide a repertoire of testable hypotheses for experimental validation. One of the NF-κB/RelA modulators we identified is STAT1. The inferred (STAT1, NF-κB/RelA, TG) triplets were validated by LC-selected reaction monitoring-MS and the results of STAT1 deletion in human fibrosarcoma cells. Overall, we have identified 562 NF-κB/RelA modulators, which are potential drug targets, and clarified mechanisms of achieving NF-κB/RelA multiple functions through modulators. Our approach can be readily applied to other TFs.
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555; Hefei Institute of Intelligent Machines, Chinese Academy of Sciences, Hefei 230031, China.
authors: Xueling
authors: X
authors: Li
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Center for Clinical Proteomics, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Yingxin
authors: Y
authors: Zhao
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Departments of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Bing
authors: B
authors: Tian
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Mohammad
authors: M
authors: Jamaluddin
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Abhishek
authors: A
authors: Mitra
authors: Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Departments of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Jun
authors: J
authors: Yang
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Maga
authors: M
authors: Rowicka
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Center for Clinical Proteomics, University of Texas Medical Branch, Galveston, Texas 77555; Departments of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors: Allan R
authors: AR
authors: Brasier
authors: Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555; Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555. Electronic address: askudlic@utmb.edu.
authors: Andrzej
authors: A
authors: Kudlicki
mesh_terms: D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D005786:Gene Expression Regulation / Q000502:physiology*; D011336:Probability; D053719:Tandem Mass Spectrometry; D051996:Transcription Factor RelA / Q000502:physiology*
chemical_list: D051996:Transcription Factor RelA
keywords: Action Mode of Modulation; Computational Biology; Functional Genomics; Gene Expression; Modulatory Network; NF-κB Transcription Factor; Proteomics; Transcription Regulation; Transcription Target Genes