Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts

He, Ye; Tsou, Pei‐Suen; Khanna, Dinesh; Sawalha, Amr H.

doi:10.1136/annrheumdis-2018-213022

Cited by 45 publications

(53 citation statements)

References 53 publications

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“…Interestingly, we identified three significant DMG that were closely related to epigenetic modification, namely FTSJ1, coding for 2'-O-methyltransferase [38], FIRRE, a long non-coding RNA shown to be associated with histone H3 lysine 27 trimethylation [39], and MECP2, coding for methyl CpG binding protein 2 and regulating gene expression by modifying chromatin [40]. Interestingly, MECP2 has been reported to be involved in SSc skin fibrosis [41]. Aberrant methylation patterns in these epigenetic regulators suggests that the epigenetic regulatory mechanism in SSc is more complex and hierarchical than previously appreciated.…”

Section: Ssc-cd4+ T Cells and Fibroblastsmentioning

confidence: 99%

Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis

Klein²,

Colmegna

et al. 2019

Preprint

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Section: Ssc-cd4+ T Cells and Fibroblastsmentioning

confidence: 99%

Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis

Klein²,

Colmegna

et al. 2019

Preprint

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“…Serpine1 is also itself a pro-inflammatory molecule as it activates macrophages (Gupta et al, 2016). Another plasminogen activator involved in the fibrotic pathway (He et al, 2018) upregulated following SCI in Mus was Plau, which could supplement the effects of Serpine1 on fibrosis. In addition to the role these TGFβ1 induced genes play in fibrosis, the activity of plasmin generated by their proteolytic activity is also involved in proteolysis of the ECM which itself could release TGFβ (Deryugina & Quigley, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Serpine 1, a major physiological regulator of the plasmin-based cascade involved in fibrotic disorders and pro-inflammatory molecule(Gupta, Xu, Castellino, & Ploplis, 2016) was upregulated post-SCI to a greater extent in Mus than Acomys (t(4)=6.441, P=0.0015). Plau, another plasminogen activator involved in the fibrotic pathway(He, Tsou, Khanna, & Sawalha, 2018) was also upregulated in Mus (t(4)=2.516, P=0.0328;…”

mentioning

confidence: 99%

Molecular and histologic outcomes following spinal cord injury in spiny mice,Acomys cahirinus

Streeter

Sunshine

Brant

et al. 2019

Preprint

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The spiny mouse (Acomys cahirinus) appears to be unique among mammals by showing little scarring or fibrosis after skin or muscle injury, but the Acomys response to spinal cord injury (SCI) is unknown. We tested the hypothesis that Acomys would have molecular and immunohistochemical evidence of reduced spinal inflammation and fibrosis following SCI as compared to C57BL/6 mice (Mus), which similar to all mammals studied to date exhibits spinal scarring following SCI. Initial experiments used two pathway-focused RT-PCR gene arrays ("wound healing" and "neurogenesis") to evaluate tissue samples from the C2-C6 spinal cord 3days after a C3/C4 hemi-crush injury (C3Hc). Based on the gene array, specific genes were selected for RT-qPCR evaluation using species-specific primers. The results supported our hypothesis by showing increased inflammation and fibrosis related gene expression (Serpine 1, Plau, Timp1) in Mus as compared to Acomys (P<0.05). RT-qPCR also showed enhanced stem cell and axonal guidance related gene expression (Bmp2, GDNF, Shh) in Acomys compared to Mus (P<0.05). Immunohistochemical evaluation of the spinal lesion at 4-wks post-injury indicated reduced collagen IV immunostaining in Acomys (P<0.05). Glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1(IBA1) immunostaining indicated morphological differences in the appearance of astrocytes and macrophages/microglia in Acomys. Collectively, the molecular and histologic results support the hypothesis that Acomys has reduced spinal inflammation and fibrosis following SCI. We suggest that Acomys may be a useful comparative model to study adaptive responses to SCI. Highlights• Spiny mice (Acomys cahirinus) and C57BL/6 (Mus) were studied after spinal injury • RT-PCR gene arrays suggested different molecular response in Acomys• RTq-PCR with species-specific primers showed increased neurogenesis-related signaling • Histology indicates reduced scarring and fibrosis in Acomys • Acomys may be a useful comparative model to study SCI

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“…Thus, the role of MeCP2 in regulating target gene expression is complicated. MeCP2 was reported to be involved in various fibrotic diseases, including lung fibrosis, 14 liver fibrosis, 15 and scleroderma 16 …”

Section: Introductionmentioning

confidence: 99%

“…In the cellular model of scleroderma, 16 MeCP2 is reported to mediate antifibrotic effects. However, in the animal model of lung fibrosis, MeCP2 was reported to be profibrotic and MeCP2‐deficient mice showed reduced fibrotic response to bleomycin‐induced lung fibrosis 14 .…”

Section: Introductionmentioning

confidence: 99%

MeCP2 epigenetically regulates alpha‐smooth muscle actin in human lung fibroblasts

Xiang

Zhou

et al. 2020

J of Cellular Biochemistry

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Background: A critical feature for fibroblasts differentiation into myofibroblasts is the expression of alpha-smooth muscle actin (α-SMA) during the tissue injury and repair process. The epigenetic mechanism, DNA methylation, is involved in regulating α-SMA expression. It is not clear how methyl-CpG-binding protein 2 (MeCP2) interacts with CpG-rich region in α-SMA, and if the CpG methylation status would affect MeCP2 binding and regulation of α-SMA expression.Methods: The association of MeCP2 with α-SMA CpG rich region were examined by chromatin immunoprecipitation (ChIP) assays in primary fibroblasts from idiopathic pulmonary fibrosis (IPF) and non-IPF control individuals, and in the lung fibroblasts treated with profibrotic cytokine transforming growth factor β1 (TGF-β1). The regulation of α-SMA by MeCP2 was examined by knocking down MeCP2 with small interfering RNA (siRNA).To explore the effects of the DNA methylation status of the CpG rich region on α-SMA expression, the cells were treated with DNA methyltransferase inhibitor, 5′-azacytidine (5′-aza). The expression of α-SMA was examined by Western blot and quantitative polymerase chain reaction, the association with MeCP2 was assessed by ChIP assays, and the methylation status was checked by bisulfate sequencing. Results:The human lung fibroblasts with increased α-SMA showed an enriched association of MeCP2, while knockdown MeCP2 by siRNA reduced α-SMA upregulation by TGF-β1. The 5′-Aza-treated cells have decreased α-SMA expression with reduced MeCP2 association. However, bisulfite sequencing revealed that most CpG sites are unmethylated despite the different expression levels of α-SMA after being treated by TGF-β1 or 5′-aza. Conclusion: Our data indicate that the methyl-binding protein MeCP2 is critical for α-SMA expression in human lung myofibroblast, and the DNA methylation status at the CpG rich region of α-SMA is not a determinative factor for its inducible expression.

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Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts

Abstract: This study demonstrates a novel role for MeCP2 in skin fibrosis and identifies MeCP2-regulated genes associated with fibroblast migration, myofibroblast differentiation and extracellular matrix degradation, which can be potentially targeted for therapy in SSc.

Cited by 45 publications

References 53 publications

Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis

Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis

Molecular and histologic outcomes following spinal cord injury in spiny mice,Acomys cahirinus

MeCP2 epigenetically regulates alpha‐smooth muscle actin in human lung fibroblasts

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