Tumor Necrosis Factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes

• Published in: PloS one Vol. 12; no. 7; p. e0179762
• Main Authors: Loupasakis, Konstantinos, Kuo, David, Sokhi, Upneet K, Sohn, Christopher, Syracuse, Bethany, Giannopoulou, Eugenia G, Park, Sung Ho, Kang, Hyelim, Rätsch, Gunnar, Ivashkiv, Lionel B, Kalliolias, George D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.07.2017; Public Library of Science (PLoS)
• Subjects: Analysis; Arthritis; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Bioinformatics; Biology; Biology and life sciences; Cells, Cultured; Chemokines - genetics; Chemokines - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cytokines; Cytokines - genetics; Cytokines - metabolism; Decay; Dynamic stability; Fibroblasts; Fibroblasts - cytology; Gene expression; Gene Expression Regulation - drug effects; Gene sequencing; Genes; Genetic aspects; Genomes; Genomics; Humans; Inflammation; Interleukin 6; Interleukin 8; Interleukin-6 - genetics; Interleukin-6 - metabolism; Kinases; MAP kinase; Matrix Metalloproteinase 3 - genetics; Matrix Metalloproteinase 3 - metabolism; Medicine and Health Sciences; Messenger RNA; Molecular modelling; Monocyte chemoattractant protein 1; mRNA stability; mRNA turnover; Necrosis; Proteins; Real-Time Polymerase Chain Reaction; Regulations; Research and analysis methods; Rheumatoid arthritis; Ribonucleic acid; RNA; RNA - chemistry; RNA - isolation & purification; RNA - metabolism; RNA sequencing; RNA Stability - drug effects; RNA, Messenger - metabolism; Sequence Analysis, RNA; Stabilization; Studies; Surgery; Switches; Synoviocytes; Synoviocytes - cytology; Synoviocytes - drug effects; Synoviocytes - metabolism; Synovitis; Temporal variations; Transcription; Transcription (Genetics); Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179762

During rheumatoid arthritis (RA), Tumor Necrosis Factor (TNF) activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF-induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.