Epigenetics and pathogenesis of systemic sclerosis; the ins and outs

Aslani, Saeed; Sobhani, Soheila; Gharibdoost, Farhad; Jamshidi, Ahmadreza; Mahmoudi, Mahdi

doi:10.1016/j.humimm.2018.01.003

Cited by 30 publications

(22 citation statements)

References 138 publications

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“…The distinct anatomical location and proposed role of environmental factors such as excessive alcohol consumption (13), heavy manual labor, and exposure to vibrations (14) suggest epigenetic regulation is likely to be important in the pathogenesis of the disease. Epigenetic mechanisms have been shown to be crucial mediators of fibrotic gene expression in a wide range of fibrotic disorders (15), including cardiac fibrosis (16), liver fibrosis (17), and systemic sclerosis (18), and probably account for the persistence of myofibroblasts in disease (19).…”

mentioning

confidence: 99%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

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mentioning

confidence: 99%

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Williams

McCann

Cabrita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Accumulating evidence has shown that many miRNAs are also critically involved in the pathogenesis of human tissue fibrosis of in several organs [40]. In the development of fibrosis in SSc, the existence of a pro-fibrosis or anti-fibrosis role has been recognized for selected microRNAs that regulate the well-known pro-fibrotic factor, TGF-β, or directly target the predicted fibrotic genes [41].…”

Section: Discussionmentioning

confidence: 99%

MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor

Shi

Liu

et al. 2018

Cell Cycle

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Systemic sclerosis (SSc) is a multisystemic fibrotic disease characterized by excessive collagen deposition and extracellular matrix synthesis. Though transforming growth factor-β (TGF-β) plays a fundamental role in the pathogenesis of SSc, the mechanism by which TGF-β signaling acts in SSc remains largely unclear. Here, we showed that TGF-β type II receptor (TGFBR2) was significantly upregulated in both human SSc dermal tissues and primary fibroblasts. In fibroblasts, siRNA-induced knockdown of TGFBR2 resulted in a reduction of p-SMAD2/3 levels and reduced production of type I collagen. Additionally, functional experiments revealed that downregulation of TGFBR2 yielded an anti-growth effect on fibroblasts through inhibiting cell cycle progression. Further studies showed that miR-3606-3p could directly target the 3'-UTR of TGFBR2 and significantly decrease the levels of both TGFBR2 mRNA and protein. Furthermore, SSc dermal tissues and primary fibroblasts contain significantly reduced amounts of miR-3606-3p, and the overexpression of miR-3606-3p in fibroblasts replicates the phenotype of TGFBR2 downregulation. Collectively, our findings demonstrated that increased TGFBR2 could be responsible for the hyperactive TGF-β signaling observed in SSc. Moreover, we identified a pivotal role for miR-3606-3p in SSc, which acts, at least partly, through the attenuation of TGF-β signaling via TGFBR2 repression, suggesting that the regulation of miR-3606-3p/TGFBR2 could be a promising therapeutic target that could improve the treatment strategy for fibrosis.

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“…Epigenetic changes are heritable alterations of the human genome affecting the gene expression without involving changes of the underlying DNA sequences. As the pathogenesis of SSc is thought to be influenced by environmental factors affecting human genome, these stimuli have been considered to be responsible for epigenetic regulatory complex changes which can manifest in alterations in disease outcomes (Aslani et al, 2018 ). RNA interference via microRNAs is considered to be one of the potential mechanisms to initiate and maintain epigenetic changes.…”

Section: Micrornasmentioning

confidence: 99%

Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

et al. 2018

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Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.

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Epigenetics and pathogenesis of systemic sclerosis; the ins and outs

Cited by 30 publications

References 138 publications

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor

Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach

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