Date: Monday, November 9, 2020
Session Type: Poster Session D
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic sclerosis (SSc) is characterised by tissue fibrosis of the major organs of the body including the skin, lungs and heart. We have previously reported that the lncRNA HOTAIR plays a central role in the activation of SSc myofibroblasts, the key cellular elements of fibrosis. HOTAIR induces fibroblast activation though H3K27me3 mediated activation of the Notch signalling pathway. Here we aimed to identify the signalling events downstream of Notch that drive SSc myofibroblast activation.
Methods: Patient fibroblasts were obtained from full thickness forearm skin biopsies of 3 adult patients with SSc of recent onset. The lncRNA HOTAIR was expressed in healthy dermal fibroblasts by lentiviral transduction. Hedgehog signalling pathway was inhibited with GANT61 and GLI2 siRNA. Gamma secretase inhibitors RO4929097 and DAPT were used to block Notch signalling. GSK126/503 were used to inhibit Enhancer of Zeste 2 (EZH2).
Results: Overexpression of HOTAIR in dermal fibroblasts induced the expression of the Hedgehog pathway transcription factor GLI2. This is mediated by activation of Notch signalling following epigenetic downregulation of miRNA-34a expression. Inhibition of H3K27 methylation and Notch signalling reduced expression of GLI2 in HOTAIR expressing fibroblasts as well as in SSc dermal fibroblasts. Importantly, the inhibition of GLI2 function using GANT61 or siRNA mitigates the pro-fibrotic phenotype induced by HOTAIR.
Conclusion: Our data indicates that GLI2 expression is stably upregulated in SSc myofibroblasts through HOTAIR and that GLI2 mediates expression of pro-fibrotic markers downstream of Notch.
To cite this abstract in AMA style:Wasson C, Ross R, Wells R, Corinaldesi C, Georgiou I, Riobo-Del Galdo N, Del Galdo F. Long Non-coding RNA HOTAIR Induces GLI2 Expression Through Notch Signalling in Systemic Sclerosis Dermal Fibroblasts [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/long-non-coding-rna-hotair-induces-gli2-expression-through-notch-signalling-in-systemic-sclerosis-dermal-fibroblasts/. Accessed May 15, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/long-non-coding-rna-hotair-induces-gli2-expression-through-notch-signalling-in-systemic-sclerosis-dermal-fibroblasts/