Long non-coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization

2016 ◽  
Vol 25 (2) ◽  
pp. 131-136 ◽  
Author(s):  
Zhongzhi Wang ◽  
Masatoshi Jinnin ◽  
Kayo Nakamura ◽  
Miho Harada ◽  
Hideo Kudo ◽  
...  
Keyword(s):  
Dermal Fibroblasts ◽  
Mrna Stabilization ◽  
Collagen Mrna ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals The Long Non-Coding RNA LncRNA8975-1 is Upregulated in Hypertrophic Scar Fibroblasts and Controls Collagen Expression

2016 ◽  
Vol 40 (1-2) ◽  
pp. 326-334 ◽  
Author(s):  
Jun Li ◽  
Ling Chen ◽  
Chunyu Cao ◽  
Hui Yan ◽  
Bei Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hypertrophic Scar ◽  
Smooth Muscle Actin ◽  
Scar Formation ◽  
Dermal Fibroblasts ◽  
Alpha Smooth Muscle Actin ◽  
Protein Levels ◽  
Reverse Transcription Pcr ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Background/Aims: Long non-coding RNAs (lncRNAs) are thought to play crucial roles in human diseases. However, the function of lncRNAs in hypertrophic scar formation remains poorly understood. Methods: In this study, we investigated the expression of lncRNA8975-1 in hypertrophic scar tissues and fibroblasts by quantitative reverse transcription PCR (qRT-PCR). To investigate its function, overexpression and knockdown of lncRNA8975-1 were performed using lentivirus infection and Stealth RNAi transfection, respectively. Cell proliferation was detected by CCK-8 assay. The protein levels of collagens and alpha-smooth muscle actin (α-SMA) were analysed by western blot. Results: We found that lncRNA8975-1 was overexpressed in hypertrophic scar tissues and dermal fibroblasts. Overexpression of lncRNA8975-1 inhibited cell proliferation and reduced the protein expression levels of COL1A2, COL1A1, COL3A1 and α-SMA in hypertrophic scar fibroblasts, whereas knockdown of lncRNA8975-1 had the opposite effect. Conclusion: Our results show that the long non-coding RNA lncRNA8975-1 is upregulated in hypertrophic scar fibroblasts; furthermore, it inhibits fibroblast proliferation and reduces collagen and α-SMA expression. Further studies on the mechanisms regulated by lncRNA8975-1 would lead to a better understanding of the pathogenesis of hypertrophic scar formation.

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

2020 ◽  
Vol 79 (4) ◽  
pp. 507-517 ◽  
Author(s):  
Christopher W Wasson ◽  
Giuseppina Abignano ◽  
Heidi Hermes ◽  
Maya Malaab ◽  
Rebecca L Ross ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Target Genes ◽  
Dermal Fibroblast ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Dermal Fibroblasts ◽  
Non Coding Rna ◽  
Skin Biopsies ◽  
Long Non Coding Rna

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.

scholarly journals O30 Long non-coding RNA HOTAIR induces beta catenin expression in systemic sclerosis through EZH2 dependent repression of Axin-2

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Christopher W Wasson ◽  
Giuseppina Abignano ◽  
Rebecca Ross ◽  
Francesco Del Galdo
Keyword(s):  
Systemic Sclerosis ◽  
Smooth Muscle Actin ◽  
Specific Inhibitor ◽  
Dermal Fibroblasts ◽  
Wnt Signalling ◽  
Beta Catenin ◽  
Cultured Fibroblasts ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Background Fibroblasts explanted from affected tissues in systemic sclerosis (SSc) maintain their pro-fibrotic phenotype in vitro. This includes increased secretion of collagens and other extracellular matrix proteins and increased proportion of α-Smooth Muscle Actin (α-SMA) positive cells (myofibroblasts). It has been previously shown that among their profibrotic features, myofibroblasts display activation of WNT signalling, which is linked to a decreased basal expression of AXIN2. Here we aimed to determine whether specific long non-coding RNA (lncRNAs) expressed in myofibroblasts could drive the epigenetically stable decreased expression of Axin 2 in vitro. Methods Full thickness skin biopsies were surgically obtained from the forearms of twelve adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted from the fibroblast cultures. Laser capture was performed to isolate cells expressing or not α-SMA as a marker of myofibroblast differentiation. LncRNA HOTAIR was overexpressed in healthy dermal fibroblasts by lentiviral induction. EZH2 was blocked in cultured fibroblasts with the specific inhibitor GSK126. Results HOTAIR expression was increased in SSc patients’ skin (100 fold) and in SSc explanted fibroblasts (5 fold; p < 0.001 for both). Further, laser captured α-SMA expressing fibroblasts expressed in average 2.5 fold higher HOTAIR RNA levels compared to α -SMA negative cells from the same donors (P < 0.05). In vitro, lentiviral induced stable overexpression of HOTAIR in healthy dermal fibroblasts led to their profibrotic activation, including significantly increased expression of Col1A1 and α-SMA both at mRNA and protein levels (2.8 and 1.8 fold respectively, p < 0.05). We further showed that HOTAIR-induced profibrotic activation was due to EZH2 dependent spread of H3k27me3 methylation marker, as demonstrated by complete inhibition by treatment with GSK126. HOTAIR driven EZH2 histone methylation suppressed the expression of Axin 2 in SSc fibroblasts. The reduced Axin 2 levels led to stabilisation of beta catenin and WNT signalling pathway activation. Conclusion Here we show that the epigenetically stable activation of SSc dermal fibroblasts is due to HOTAIR. We also identified a major downstream target of HOTAIR is Axin-2. The results of these studies identify a new venue to modulate fibroblasts biology which could inform clinical research to resolve chronic fibrosis and re-establish tissue homeostasis in SSc. Disclosures C.W. Wasson None. G. Abignano None. R. Ross None. F. Del Galdo Consultancies; AstraZeneca, GSK, Boehringer-Ingelheim, Actelion, Capella Biosciences, Chemomab.

Innate immune responses and type 1 diabetes: A role for a long non-coding RNA?

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
MP Ashton ◽  
I Tan ◽  
L Mackin ◽  
C Elso ◽  
E Chu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Long non-coding RNA expression profiles in human parathyroid tumors

2017 ◽  
Author(s):  
Annamaria Morotti ◽  
Irene Forno ◽  
Valentina Andre ◽  
Andrea Terrasi ◽  
Chiara Verdelli ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Rna Expression ◽  
Parathyroid Tumors ◽  
Non Coding Rna ◽  
Long Non Coding Rna

The Variant rs145204276 of GAS5 is Associated with the Development and Prognosis of Gastric Cancer

2018 ◽  
Vol 27 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Qianjun Li ◽  
Gang Ma ◽  
Huimin Guo ◽  
Suhua Sun ◽  
Ying Xu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Rate ◽  
Cancer Progression ◽  
Regulatory Mechanism ◽  
Tumor Stage ◽  
Kaplan Meier ◽  
Non Coding Rna ◽  
Early Tumor ◽  
Long Non Coding Rna ◽  
Clinicopathological Variables

Background & Aims: Down-regulation of the growth arrest specific transcript 5 (GAS5) (long non-coding RNA) is associated with cell proliferation of gastric cancer (GC) and a poor prognosis. We aimed to investigate whether the variant rs145204276 of GAS5 is associated with the prognosis of GC in the Chinese population, and to unveil the regulatory mechanism underlying the GAS5 expression in GC tissues.Method: 1,253 GC patients and 1,354 healthy controls were included. The frequency of the genotype del/del and the allele del of rs145204276 were compared between the patients and the controls and between different subgroups of patients classified by clinicopathological variables. The overall survival rate was analyzed according to the Kaplan-Meier method using the log-rank test.Results: The frequency of genotype del/del was significantly lower in patients than in the controls (7.0% vs. 9.1%, p = 0.001). Kaplan-Meier analysis showed that genotype del/del was significantly associated with a higher survival rate (p = 0.01). Patients with late tumor stage were found to have a significantly lower rate of genotype del/del than those with an early tumor stage (4.9% vs. 8.8%, p = 0.01). Patients with UICC III and IV were found to have a significantly lower rate of genotype del/del than those with UICC I and II (5.3% vs. 8.1%, p = 0.02).Conclusion: The variant rs145204276 of GAS5 is associated with the development and prognosis of GC. The allele del of rs145204276 is associated with a remarkably lower incidence of cancer progression and metastasis.

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