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The molecular basis for dysregulated activation of NKX2-5 in vascular remodelling of systemic sclerosis

Dritsoula, A; Papaioannou, I; Guerra, SG; Fonseca, C; Martin, J; Herrick, AL; Abraham, DJ; ... Ponticos, M; + view all (2018) The molecular basis for dysregulated activation of NKX2-5 in vascular remodelling of systemic sclerosis. Arthritis & Rheumatology , 70 (6) pp. 920-931. 10.1002/art.40419. Green open access

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Abstract

OBJECTIVE: NKX2-5 is a homeobox transcription factor required for the formation of the heart and vessels during development, with significant postnatal downregulation and reactivation in disease states characterised by vascular remodelling. In this study, we sought to investigate mechanisms that activate NKX2-5 expression in diseased vessels, such as scleroderma associated pulmonary hypertension (SSc-PH), and identify genetic variability that potentially underlies susceptibility to specific vascular complications. METHODS: We explored NKX2-5 expression in biopsies of patients with SSc-PH and in pulmonary artery smooth muscle cells (PASMC) from scleroderma patients. Disease-associated putative functional SNPs in NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein-DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing. RESULTS: Increased NKX2-5 expression in SSc-PH biopsies was localised to remodelled vessels and in SSc-PH PASMC. Meta-analysis of two independent scleroderma cohorts revealed association of rs3131917 with scleroderma (p=0.029). We demonstrated that disease-associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA6, c-JUN, and MEF-2c. We also characterised an activator/co-activator TEAD/YAP1 complex, bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating NKX2-5 transcription. CONCLUSIONS: NKX2-5 is genetically associated with scleroderma, pulmonary hypertension and fibrosis. Functional evidence revealed a regulatory mechanism which results in NKX2-5 transcriptional activation in PASMC through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2-5 activation in cardiovascular disease characterised by vascular remodelling.

Type: Article
Title: The molecular basis for dysregulated activation of NKX2-5 in vascular remodelling of systemic sclerosis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/art.40419
Publisher version: http://doi.org/10.1002/art.40419
Language: English
Additional information: Copyright © 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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 Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
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/10041939
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