Regulator combinations identify systemic sclerosis patients with more severe disease

Wang, Yue; Franks, Jennifer M; Yang, Monica; Toledo, Diana M; Wood, Tammara A.; Hinchcliff, Monique; Whitfield, Michael L.

doi:10.1172/jci.insight.137567

Cited by 4 publications

(6 citation statements)

References 56 publications

(100 reference statements)

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“…Our prior work indicated a role for the RUNX1 transcription factor in the inflammatory subtype of SSc 6 . We began this study by analyzing a larger cohort of skin biopsies from individuals with SSc and healthy controls to examine the distribution of RUNX1 expression and to further investigate its correlation with disease severity 6 . Analysis of gene expression data showed significantly increased expression of RUNX1 in lesional forearm skin biopsies from 86 individuals diagnosed with lcSSc and dcSSc 22 .…”

Section: Resultsmentioning

confidence: 82%

Section: Runx1mentioning

confidence: 82%

“…Through network analyses of transcription factor (TF) activity, we have previously shown that the runt-related transcription factor 1 ( RUNX1 ) is a key regulator in SSc. RUNX1 is highly expressed in SSc skin biopsies, particularly within the inflammatory patient subgroup, and is strongly correlated with measures of disease severity 6 .…”

Section: Introductionmentioning

confidence: 99%

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RUNX1 is Expressed in a Subpopulation of Dermal Fibroblasts and Higher RUNX1 Levels are Associated with the Severity of Systemic Sclerosis

Parvizi,

Gong,

Jarnagin

et al. 2024

Preprint

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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) is not known. Through gene expression analysis, we have demonstrated an association between the severity of dermal fibrosis and the expression levels ofRUNX1in the skin of patients with SSc. Additionally, we identified hypomethylated CpG sites proximal to theRUNX1gene, implicating their potential role in the increased expression ofRUNX1. Analysis of single-cell RNA-seq data from skin biopsies of individuals with SSc revealed thatRUNX1is higher in subpopulations of fibroblasts enriched in SSc, which are believed to contribute to fibrosis. Lastly, modulation ofRUNX1activity using an inhibitor caused a reduction in fibroblast contraction and proliferation rates. Altogether, this study is the first to demonstrate a potential role forRUNX1in the pathogenesis of systemic sclerosis dermal fibrosis.

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Section: Resultsmentioning

confidence: 82%

Section: Runx1mentioning

confidence: 82%

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RUNX1 is Expressed in a Subpopulation of Dermal Fibroblasts and Higher RUNX1 Levels are Associated with the Severity of Systemic Sclerosis

Parvizi,

Gong,

Jarnagin

et al. 2024

Preprint

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“…Top TFs in the FB3 cluster included SMAD5, SMAD3, and NFKB1, which are associated with TGF-b signaling, fibrosis, and inflammation (Fig 4B , Table 1, Table S6) (45,46). Other SScrelevant TFs that showed increased expression in FB3 include TFAP2 proteins (47) and RUNX family proteins, which were identified as enriched regions in our data, with RUNX2 ranking the highest (48). Top GO terms were associated with pathways related to ECM maintenance, response to TGF-b, wound healing, PI3K-Akt signaling pathway, and angiogenesis (Table S9).…”

Section: Clusters Maintain Distinct Biological Profiles and Highlight...mentioning

confidence: 67%

Single-cell epigenomic dysregulation of Systemic Sclerosis fibroblasts via CREB1/EGR1 axis in self-assembled human skin equivalents

Abel,

Kosarek,

Parvizi

et al. 2024

Preprint

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Systemic sclerosis (SSc) is an autoimmune disease characterized by skin fibrosis, internal organ involvement and vascular dropout. We previously developed and phenotypically characterized an in vitro 3D skin-like tissue model of SSc, and now analyze the transcriptomic (scRNA-seq) and epigenetic (scATAC-seq) characteristics of this model at single-cell resolution. SSc 3D skin-like tissues were fabricated using autologous fibroblasts, macrophages, and plasma from SSc patients or healthy control (HC) donors. SSc tissues displayed increased dermal thickness and contractility, as well as increased alpha-SMA staining. Single-cell transcriptomic and epigenomic analyses identified keratinocytes, macrophages, and five populations of fibroblasts (labeled FB1 - 5). Notably, FB1 APOE-expressing fibroblasts were 12-fold enriched in SSc tissues and were characterized by high EGR1 motif accessibility. Pseudotime analysis suggests that FB1 fibroblasts differentiate from a TGF-beta-responsive fibroblast population and ligand-receptor analysis indicates that the FB1 fibroblasts are active in macrophage crosstalk via soluble ligands including FGF2 and APP. These findings provide characterization of the 3D skin-like model at single cell resolution and establish that it recapitulates subsets of fibroblasts and macrophage phenotypes observed in skin biopsies.

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“…SSc is a heterogeneous disease characterized not only by limited and diffuse skin lesions, but also by a diverse spectrum of organ involvement, leading to significant differences in organ damage pattern, severity, progression, mortality, and treatment choices between patients [ 11 , 12 , 13 ]. Therefore, it is essential to determine the risk factors of worsening organ damage trajectories in patients with SSc.…”

Section: Introductionmentioning

confidence: 99%

Anemia Is an Indicator for Worse Organ Damage Trajectories in Patients with Systemic Sclerosis: A Retrospective Study

Jiang

et al. 2022

JCM

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It is important for clinicians to determine the risk of worsening trajectories in SSc patients. The Scleroderma Clinical Trials Consortium (SCTC) Damage Index (DI) has been developed to quantify organ damage and shows good capability for mortality and morbidity prediction in patients with SSc. This retrospective study aimed to describe the SCTC-DI in Chinese SSc patients and to find features predicting worse organ damage trajectories based on SCTC-DI. A total of 433 SSc patients who met the inclusion criteria in the Peking University Third Hospital (PKUTH-SSc) and People’s Hospital SSc cohort (PKUPH-SSc) were recruited for our study. Organ damage was relatively mild in our Chinese SSc cohort compared to other cohorts, with a mean SCTC-DI of 5.21 ± 4.60. We used both SCTC-DI ≥ 6 and ≥4 to define the high burden of organ damage and established two risk models by the LASSO algorithm, which revealed good identification of high organ damage burden (AUC = 0.689, 95% CI 0.636 to 0.742, p < 0.001 in SCTC-DI ≥ 6 model; AUC = 0.694, 95% CI 0.641 to 0.746, p < 0.001 in modified SCTC-DI ≥ 4 model). The anemia index at the baseline was included in these two models and was also independently related to organ damage progression (HR = 1.75, 95% CI 1.16 to 2.66, p = 0.008). In addition, the presence of an anti-Scl-70 autoantibody was also a predictor of progression (HR = 1.91, 95% CI 1.22 to 2.99, p = 0.005). In conclusion, anemia at the baseline was an important indicator for worse organ damage trajectories in SSc patients. We recommend using hemoglobin as a potential biomarker to evaluate organ damage in SSc patients.

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Regulator combinations identify systemic sclerosis patients with more severe disease

Cited by 4 publications

References 56 publications

RUNX1 is Expressed in a Subpopulation of Dermal Fibroblasts and Higher RUNX1 Levels are Associated with the Severity of Systemic Sclerosis

RUNX1 is Expressed in a Subpopulation of Dermal Fibroblasts and Higher RUNX1 Levels are Associated with the Severity of Systemic Sclerosis

Single-cell epigenomic dysregulation of Systemic Sclerosis fibroblasts via CREB1/EGR1 axis in self-assembled human skin equivalents

Anemia Is an Indicator for Worse Organ Damage Trajectories in Patients with Systemic Sclerosis: A Retrospective Study

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