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Publication Detail
The molecular basis for dysregulated activation of NKX2-5 in vascular remodelling of systemic sclerosis.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Dritsoula A, Papaioannou I, Guerra SG, Fonseca C, Martin J, Herrick AL, Abraham DJ, Denton CP, Ponticos M
  • Publication date:
    17/01/2018
  • Journal:
    Arthritis & rheumatology (Hoboken, N.J.)
  • Medium:
    Print-Electronic
  • Status:
    Published
  • Print ISSN:
    2326-5191
  • Language:
    eng
  • Addresses:
    Centre for Rheumatology and Connective Tissue Diseases, Division of Medicine, University College London, London, UK.
Abstract
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.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.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.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. This article is protected by copyright. All rights reserved.
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