Annals of the rheumatic diseases · 2025
RUNX1 is expressed in a subpopulation of dermal fibroblasts and is associated with disease severity of systemic sclerosis.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Parvizi Rezvan, Gong Zhiyun, Jarnagin Helen C, Toledo Diana M, Abel Tamar R, Popovich Dillon, Morrisson Madeline J, Wood Tammara A, Shenk Sasha, Sarkar Mrinal K, Plazyo Olesya, Dey Poulami, Coon Anthony, Erba Jake M, Tsoi Lam C, Tsou Pei-Suen, Hinchcliff Monique E, Khanna Dinesh, Garlick Jonathan A, Gudjonsson Johann E, Pioli Patricia A, Whitfield Michael L
Аннотация
OBJECTIVES: The activation of runt-related transcription factor 1 (RUNX1) in fibroblasts has been implicated in wound healing and fibrosis; however, the role of RUNX1 in the fibrotic progression of the autoimmune disease systemic sclerosis (SSc) remains known.
METHODS: Leveraging gene expression, genome-wide DNA methylation, and single-cell resolution data of SSc skin and fibroblast, we analysed the impact of RUNX1 dysregulation in SSc dermal fibrosis. RUNX1 function was subsequently assessed using siRNA, pharmacologic inhibition, and CRISPR knockout in 2-dimensional and 3-dimensional fibroblast cultures.
RESULTS: Analysis of gene expression in multiple cohorts demonstrated an association between the severity of dermal fibrosis and the expression levels of RUNX1 in the skin of patients with SSc. Epigenomic analyses of methylation identified hypomethylated 5-Cytosine-phosphate-Guanine-3 (CpG) sites proximal to the RUNX1 gene, implicating their potential role in the increased expression of RUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed that RUNX1 is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. RUNX1 CRISPR knockout resulted in reduced alpha smooth muscle actin expression. Inhibition of RUNX1 activity caused a reduction in fibroblast activation, contraction, extracellular matrix components, and proliferation rates, including a reduction in SFRP4, LUM, and COL1A1.
CONCLUSIONS: This study is the first to demonstrate a potential role for RUNX1 in the pathogenesis of SSc dermal fibrosis. RUNX1 is associated with more severe SSc fibrosis and is associated with a subpopulation of dermal fibroblasts implicated in fibrosis.
METHODS: Leveraging gene expression, genome-wide DNA methylation, and single-cell resolution data of SSc skin and fibroblast, we analysed the impact of RUNX1 dysregulation in SSc dermal fibrosis. RUNX1 function was subsequently assessed using siRNA, pharmacologic inhibition, and CRISPR knockout in 2-dimensional and 3-dimensional fibroblast cultures.
RESULTS: Analysis of gene expression in multiple cohorts demonstrated an association between the severity of dermal fibrosis and the expression levels of RUNX1 in the skin of patients with SSc. Epigenomic analyses of methylation identified hypomethylated 5-Cytosine-phosphate-Guanine-3 (CpG) sites proximal to the RUNX1 gene, implicating their potential role in the increased expression of RUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed that RUNX1 is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. RUNX1 CRISPR knockout resulted in reduced alpha smooth muscle actin expression. Inhibition of RUNX1 activity caused a reduction in fibroblast activation, contraction, extracellular matrix components, and proliferation rates, including a reduction in SFRP4, LUM, and COL1A1.
CONCLUSIONS: This study is the first to demonstrate a potential role for RUNX1 in the pathogenesis of SSc dermal fibrosis. RUNX1 is associated with more severe SSc fibrosis and is associated with a subpopulation of dermal fibroblasts implicated in fibrosis.