Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

Chen, Xin; Li, Wanxia; Chen, Yu; Li, Xiaofeng; Li, Hai-Di; Huang, Huimin; Bu, Fang-tian; Pan, Xue‐Yin; Yang, Yang; Huang, Cheng; Meng, Xiao‐Ming; Li, Jun

doi:10.1038/s41419-018-1032-9

Cited by 51 publications

(28 citation statements)

References 34 publications

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“…In EBi3 -/mice, infection caused an increase in DNA demethylation and analyzing EBi3 -/-C versus EBi3 -/-I we can see that TET1 plays the major differences observed in S2, but TET2 and TET3 also increased strongly their expression values. The literature lacks data about methylation and demethylation of DNA in hepatic tissues during schistosomiasis, but considering other disease that affect the liver causing collagen deposition, there is an increase in liver methylation during hepatic fibrosis development, as determined by analyzing the overall methylation and the methylation of specific genes (Septina9, Long non-coding RNA H19, SUN2) in diseases such as hepatocarcinoma, hepatitis and cirrhosis [10,11,28], this occurred in our control groups WTC and WTI considering the qRT-PCR data.…”

Section: Discussionmentioning

confidence: 99%

“…These changes are fundamental for gene expression regulation, sex X chromosome silencing in females, transposon silencing [8,9]. Diseases that affect the liver causing collagen deposition induct alterations in the expression of DNA methyltransferases and DNA demethylases, leading to disturbance in expression of several genes [10,11], here we intended evaluate in schistosomiasis. DNMT1 enzyme is related to the maintenance of existing methylation during the replication process, copying the patterns from the template to the new strand, and is more expressed in the period before mitosis.…”

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confidence: 99%

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Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni

et al. 2020

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Schistosoma mansoni adaptive success is related to regulation of replication, transcription and translation inside and outside the intermediate and definitive host. We hypothesize that S. mansoni alters its epigenetic state in response to the mammalian host immune system, reprogramming gene expression and altering the number of eggs. In response, a change in the DNA methylation profile of hepatocytes could occurs, modulating the extent of hepatic granuloma. To investigate this hypothesis, we used the EBi3 -/murine (Mus musculus) model of S. mansoni infection and evaluated changes in new and maintenance DNA methylation profiles in the liver after 55 days of infection. We evaluated expression of epigenetic genes and genes linked to histone deubiquitination in male and female S. mansoni worms. Comparing TET expression with DNMT expression indicated that DNA demethylation exceeds methylation in knockout infected and uninfected mice and in wild-type infected and uninfected mice. S. mansoni infection provokes activation of demethylation in EBi3 -/-I mice (knockout infected). EBi3 -/-C (knockout uninfected) mice present intrinsically higher DNA methylation than WTC (control uninfected) mice. EBi3 -/-I mice show decreased hepatic damage considering volume and reduced number of granulomas compared to WTI mice; the absence of IL27 and IL35 pathways decreases the Th1 response resulting in minor liver damage. S. mansoni males and females recovered from EBi3 -/-

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni

et al. 2020

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“…It has been shown that 5-azadC, an inhibitor of DNA methyltransferase, can block the enzymatic activity of all three methyltransferases 32. We have previously demonstrated that 5-azadC could reduce liver injury and inhibit the expression of COL1a1 and α-SMA in primary HSCs 33. To investigate whether the down-regulated expression of RCAN1.4 in activated HSCs was attributed to DNA methylation, 5-azadC 34 and DNMTs-RNAi were employed.…”

Section: Resultsmentioning

confidence: 99%

Methylation of RCAN1.4 mediated by DNMT1 and DNMT3b enhances hepatic stellate cell activation and liver fibrogenesis through Calcineurin/NFAT3 signaling

Pan

You

et al. 2019

Theranostics

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Background : Liver fibrosis is characterized by extensive deposition of extracellular matrix (ECM) components in the liver. RCAN1 (regulator of calcineurin 1), an endogenous inhibitor of calcineurin (CaN), is required for ECM synthesis during hypertrophy of various organs. However, the functional role of RCAN1 in liver fibrogenesis has not yet been addressed. Methods : We induced experimental liver fibrosis in mice by intraperitoneal injection of 10 % CCl 4 twice a week. To investigate the functional role of RCAN1.4 in the progression of liver fibrosis, we specifically over-expressed RCAN1.4 in mice liver using rAAV8-packaged RCAN1.4 over-expression plasmid. Following the establishment of the fibrotic mouse model, primary hepatic stellate cells were isolated. Subsequently, we evaluated the effect of RCAN1.4 on hepatic fibrogenesis, hepatic stellate cell activation, and cell survival. The biological role and signaling events for RCAN1 were analyzed by protein-protein interaction (PPI) network. Bisulfite sequencing PCR (BSP) was used to predict the methylated CpG islands in the RCAN1.4 gene promoter. We used the chromatin immunoprecipitation (ChIP assay) to investigate DNA methyltransferases which induced decreased expression of RCAN1.4 in liver fibrosis. Results : Two isoforms of RCAN1 protein were expressed in CCl 4 -induced liver fibrosis mouse model and HSC-T6 cells cultured with transforming growth factor-beta 1 (TGF-β1). RCAN1 isoform 4 (RCAN1.4) was selectively down-regulated in vivo and in vitro . The BSP analysis indicated the presence of two methylated sites in RCAN1.4 promoter and the downregulated RCAN1.4 expression levels could be restored by 5-aza-2'-deoxycytidine (5-azadC) and DNMTs-RNAi transfection in vitro . ChIP assay was used to demonstrate that the decreased RCAN1.4 expression was associated with DNMT1 and DNMT3b. Furthermore, we established a CCl 4 -induced liver fibrosis mouse model by injecting the recombinant adeno-associated virus-packaged RCAN1.4 (rAAV8-RCAN1.4) over-expression plasmid through the tail vein. Liver- specific-over-expression of RAN1.4 led to liver function recovery and alleviated ECM deposition. The key protein (a member of the NFAT family of proteins) identified on PPI network data was analyzed in vivo and in vitro . Our results demonstrated that RCAN1.4 over-expression alleviates, whereas its knockdown exacerbates, TGF-β1-induced liver fibrosis in vitro in a CaN/NFAT3 signaling-dependent manner. Conclusions : RCAN1.4 could alleviate liver fibrosis through inhibition of CaN/NFAT3 signaling, and the anti-fibrosis function of RCAN1.4 could be blocked by DNA methylation mediated by DNMT1 and DNMT3b. Thus, RCAN1.4 may serve as a potential therapeutic target in the treatment of liver f...

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“…Unlike the genome of an organism, the epigenome is not a consistent entity and may be modulated by different intrinsic, chemical, and environmental cues [87], and its changes may be inherited across generations [88]. DNA methyltransferases (DNMTs), such as DNMT1, DNMT3a, and DNMT3b, enable DNA methylation, which is correlated with the conversion of quiescent HSC into hepatic myofibroblasts [89]. DNA methylation inhibitors exert a regulatory effect on hepatic wound healing and fibrogenesis [90,91].…”

Section: Mir-29a Functions As An Epigenetic Modifier To Mitigate Livementioning

confidence: 99%

The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond

Lin

Yang

Wang

et al. 2020

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and ranges from steatosis to steatohepatitis and to liver fibrosis. Lipotoxicity in hepatocytes, elevated oxidative stress and the activation of proinflammatory mediators of Kupffer cells, and fibrogenic pathways of activated hepatic stellate cells can contribute to the development of NAFLD. MicroRNAs (miRs) play a crucial role in the dysregulated metabolism and inflammatory signaling connected with NAFLD and its progression towards more severe stages. Of note, the protective effect of non-coding miR-29a on liver damage and its versatile action on epigenetic activity, mitochondrial homeostasis and immunomodulation may improve our perception of the pathogenesis of NAFLD. Herein, we review the biological functions of critical miRs in NAFLD, as well as highlight the emerging role of miR-29a in therapeutic application and the recent advances in molecular mechanisms underlying its liver protective effect.

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Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

Cited by 51 publications

References 34 publications

Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni

Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni

Methylation of RCAN1.4 mediated by DNMT1 and DNMT3b enhances hepatic stellate cell activation and liver fibrogenesis through Calcineurin/NFAT3 signaling

The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond

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