Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma

Tsou, Pei‐Suen; Campbell, Phillip L.; Amin, M. Asif; Coit, Patrick; Miller, Shaylynn; Fox, David A.; Khanna, Dinesh; Sawalha, Amr H.

doi:10.1073/pnas.1813006116

Cited by 82 publications

(112 citation statements)

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“…One member of the complex is the enzyme EZH2, which is essential for histone 3 trimethylation. Tsou et al have shown that EZH2 levels are increased in SSc fibroblasts and inhibition of EZH2 suppresses their profibrotic phenotype 18. Here, we set out to determine whether HOTAIR overexpression enhances expression of EZH2 and methylation of histone 3 in dermal fibroblasts.…”

Section: Resultsmentioning

confidence: 94%

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Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

et al. 2020

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BackgroundSystemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3).MethodsFull-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor.ResultsSSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro.ConclusionsOur data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling.

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Section: Resultsmentioning

confidence: 94%

“…Recently, Tsou et al 18 have shown that enhancer of zeste 2 (EZH2) plays an important role in the epigenetic features linked to tissue fibrosis in SSc. EZH2 is the enzymatic subunit of the polycomb repressor complex (PRC) that induces methylation of histone 3, therefore silencing target genes.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

et al. 2020

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“…TGFB1 is linked to Enhancer of zeste homolog 2 (EZH2) (30)(31)(32), the most overrepresented transcriptional regulator predicted to bind to the DEGs according to motif analysis and ChIP-seq reference data. EZH2 is the rate-limiting catalytic subunit of the polycomb repressive complex 2 that silences gene activity epigenetically through deposition of the repressive H3K27me3 histone mark (33).…”

Section: Discussionmentioning

confidence: 99%

The endometrial transcription landscape of MRKH syndrome

Hentrich

Koch

Weber

et al. 2020

Preprint

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The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (OMIM 277000) is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. While genetic causes have been identified for a small subset of patients and epigenetic mechanisms presumably contribute to the pathogenic unfolding, too, the etiology of the syndrome has remained largely enigmatic. A comprehensive understanding of gene activity in the context of the disease is crucial to identify etiological components and their potential interplay. So far, this understanding is lacking, primarily due to the scarcity of samples and suitable tissue.In order to close this gap, we profiled endometrial tissue of uterus rudiments in a large cohort of MRKH patients using RNA-seq and thereby provide a genome-wide view on the altered transcription landscape of the MRKH syndrome. Differential and co-expression analyses of the data identified cellular processes and candidate genes that converge on a core network of interconnected regulators that emerge as pivotal for the perturbed expression space. With these results and browsable access to the rich data through an online tool we seek to accelerate research to unravel the underlying biology of this syndrome.

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“…Bleomycin-induced skin fibrosis. The procedure to induce fibrosis by bleomycin in mice was published previously (2,13). Bleomycin was dissolved to 1 mg/ml with PBS.…”

Section: Patients and Controlsmentioning

confidence: 99%

“…Epigenetic regulation affects chromatin dynamics and thereby modulates gene transcription. In addition to DNA methylation and non-coding RNAs, histone changes are implicated in SSc fibroblast activation (2)(3)(4). Acetylation of histones on lysine residues is one of the most common histone modifications that relaxes the chromatin structure by loosening the histone-DNA interaction, which results in increased chromatin accessibility for transcription.…”

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confidence: 99%

Inhibition of histone readers bromodomain extra-terminal proteins alleviates skin fibrosis in experimental models of scleroderma

Vichaikul

et al. 2020

Preprint

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Objectives: Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription in many fibrotic diseases. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in scleroderma (SSc). Methods: Dermal fibroblasts were isolated from biopsies from healthy subjects or patients with diffuse cutaneous (dc)SSc. Fibroblasts were treated with pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. Knockdown of BETs was achieved by siRNA transfection. The in vivo anti-fibrotic efficacy of JQ1 was determined in a bleomycin-induced skin fibrosis mouse model. T-test or ANOVA were used to compare differences between groups, and a p-value of <0.05 was considered significant. Results: BET inhibitor JQ1 dose-dependently downregulated pro-fibrotic genes in dcSSc fibroblasts, and inhibited cell migration and gel contraction. It suppressed proliferation by inducing cell cycle arrest. The anti-fibrotic effects of JQ1 were also observed in TGFβ-treated normal fibroblasts. JQ1 prevented bleomycin-induced skin fibrosis in mice. The anti-fibrotic effect of JQ1 was mediated by inhibition of BRD4, as specific blockade or knockdown of BRD4 led to downregulation of fibrotic markers and inhibition of myofibroblast properties, while inhibition or knockdown of BRD2 or BRD3 had minimal effects in dcSSc fibroblasts. Conclusions: BET inhibition showed promising anti-fibrotic effects in SSc both in vitro and in vivo. Specifically, we showed that BRD4 plays a critical role in SSc fibrosis and that targeting BRD4 might be a novel therapeutic option for this disease.

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Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma

Cited by 82 publications

References 48 publications

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

The endometrial transcription landscape of MRKH syndrome

Inhibition of histone readers bromodomain extra-terminal proteins alleviates skin fibrosis in experimental models of scleroderma

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