Journal
JOURNAL OF COMPUTATIONAL BIOLOGY
Volume 22, Issue 4, Pages 300-312Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/cmb.2014.0299
Keywords
modulatory network; integrative probabilistic model; NF-kappa B; transcription factor; modulator
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Funding
- National Institutes of Health/NHLBI [N01-HV-00245, NIAID AI062885]
- National Natural Science Foundation of China [31271412, 31371340, 61273324]
- Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia (CPRIT Grant) [RP140113]
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How different pathways lead to the activation of a specific transcription factor (TF) with specific effects is not fully understood. We model context-specific transcriptional regulation as a modulatory network: triplets composed of a TF, target gene, and modulator. Modulators usually affect the activity of a specific TF at the posttranscriptional level in a target gene-specific action mode. This action may be classified as enhancement, attenuation, or inversion of either activation or inhibition. As a case study, we inferred, from a large collection of expression profiles, all potential modulations of NF-kappa B/RelA. The predicted modulators include many proteins previously not reported as physically binding to RelA but with relevant functions, such as RNA processing, cell cycle, mitochondrion, ubiquitin-dependent proteolysis, and chromatin modification. Modulators from different processes exert specific prevalent action modes on distinct pathways. Modulators from noncoding RNA, RNA-binding proteins, TFs, and kinases modulate the NF-kappa B/RelA activity with specific action modes consistent with their molecular functions and modulation level. The modulatory networks of NF-kappa B/RelA in the context epithelial-mesenchymal transition (EMT) and burn injury have different modulators, including those involved in extracellular matrix (FBN1), cytoskeletal regulation (ACTN1), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long intergenic nonprotein coding RNA, and tumor suppression (FOXP1) for EMT, and TXNIP, GAPDH, PKM2, IFIT5, LDHA, NID1, and TPP1 for burn injury.
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