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STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis post-transcriptionally and is essential for lung myofibroblast differentiation

Papaioannou, I; Xu, S; Denton, CP; Abraham, D; Ponticos, M; (2018) STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis post-transcriptionally and is essential for lung myofibroblast differentiation. Molecular Biology of the Cell , 29 (2) pp. 84-95. 10.1091/mbc.E17-06-0342. Green open access

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Abstract

Fibroblast differentiation is key cellular process that underlies the process of fibrosis, a deadly complication of fibrotic diseases like Scleroderma (SSc). This transition coincides with the overproduction of Collagen type I (COL1) and other extracellular matrix proteins. High level expression of the collagen type 1α2 subunit (COL1A2), requires the engagement of a far upstream enhancer, whose activation is strongly dependent on the AP1 factor JunB. We now report that STAT3 also binds the COL1A2 enhancer and is essential for RNA polymerase recruitment, without affecting JunB binding. STAT3 is required for the increased COL1A2 expression observed in myofibroblasts.We also report that TGFβ partially activates STAT3 and show that inhibiting STAT3 potently blocks TGFβ signalling, matrix remodelling and TGFβ-induced myofibroblast differentiation. Activation of STAT3 with IL6 trans-signalling alone however only increased COL1A2 protein expression, leaving COL1A2 mRNA levels unchanged. Our results suggest that activated STAT3 is not the limiting factor for collagen enhancer activation in human lung fibroblasts. Yet, a certain threshold level of STAT3 38 activity is essential to support activation of the COL1A2 enhancer and TGFβ signalling in fibroblasts. We propose that STAT3 operates at the post-transcriptional as well as the transcriptional level.

Type: Article
Title: STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis post-transcriptionally and is essential for lung myofibroblast differentiation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1091/mbc.E17-06-0342
Publisher version: http://dx.doi.org/10.1091/mbc.E17-06-0342
Language: English
Additional information: © 2018 Papaioannou et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
Keywords: Lung Fibrosis, Collagen regulation, Extracellular Matrix regulation, JAK/STAT signalling, Interleukin 6, Myofibroblast differentiation, Scleroderma
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10033810
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