| http://purl.uniprot.org/citations/29342503 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/29342503 | http://www.w3.org/2000/01/rdf-schema#comment | "ObjectiveNKX2-5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down-regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2-5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)-associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications.MethodsWe explored NKX2-5 expression in biopsy samples from patients with SSc-associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease-associated putative functional single-nucleotide polymorphisms (SNPs) at the 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 analyses.ResultsIncreased NKX2-5 expression in biopsy samples from patients with SSc-associated PH was localized to remodeled vessels and PASMCs. Meta-analysis of 2 independent scleroderma cohorts revealed an 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 GATA-6, c-Jun, and myocyte-specific enhancer factor 2C. We also characterized an activator/coactivator transcription-enhancer factor domain 1 (TEAD1)/Yes-associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5.ConclusionNKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs 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 characterized by vascular remodeling."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.org/dc/terms/identifier | "doi:10.1002/art.40419"xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Martin J."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Dritsoula A."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Fonseca C."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Abraham D.J."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Herrick A.L."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Guerra S.G."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Denton C.P."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Ponticos M."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/author | "Papaioannou I."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/date | "2018"xsd:gYear |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/name | "Arthritis Rheumatol"xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/pages | "920-931"xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/title | "Molecular Basis for Dysregulated Activation of NKX2-5 in the Vascular Remodeling of Systemic Sclerosis."xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://purl.uniprot.org/core/volume | "70"xsd:string |
| http://purl.uniprot.org/citations/29342503 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/29342503 |
| http://purl.uniprot.org/citations/29342503 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/29342503 |
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| http://purl.uniprot.org/uniprot/#_A0A2R4LFK0-mappedCitation-29342503 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29342503 |
| http://purl.uniprot.org/uniprot/#_A0A0S2Z383-mappedCitation-29342503 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29342503 |
| http://purl.uniprot.org/uniprot/#_A0A165EY39-mappedCitation-29342503 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29342503 |
| http://purl.uniprot.org/uniprot/#_A0A165EY55-mappedCitation-29342503 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/29342503 |