Cargando…

Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1

Accumulating evidence suggests long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Here, we aimed to define the role of HOXA transcript at the distal tip (HOTTIP) in RA pathogenesis in relation to SFRP1 methylation and Wnt signaling pathway. HOTTIP was...

Descripción completa

Detalles Bibliográficos
Autores principales: Hu, Xumin, Tang, Jianhua, Hu, Xuyun, Bao, Peng, Deng, Weixi, Wu, Jionglin, Liang, Yuwei, Chen, Zhipeng, Gao, Liangbin, Tang, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948255/
https://www.ncbi.nlm.nih.gov/pubmed/31902746
http://dx.doi.org/10.1016/j.omtn.2019.11.015
_version_ 1783485708116164608
author Hu, Xumin
Tang, Jianhua
Hu, Xuyun
Bao, Peng
Deng, Weixi
Wu, Jionglin
Liang, Yuwei
Chen, Zhipeng
Gao, Liangbin
Tang, Yong
author_facet Hu, Xumin
Tang, Jianhua
Hu, Xuyun
Bao, Peng
Deng, Weixi
Wu, Jionglin
Liang, Yuwei
Chen, Zhipeng
Gao, Liangbin
Tang, Yong
author_sort Hu, Xumin
collection PubMed
description Accumulating evidence suggests long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Here, we aimed to define the role of HOXA transcript at the distal tip (HOTTIP) in RA pathogenesis in relation to SFRP1 methylation and Wnt signaling pathway. HOTTIP was found highly expressed, and SFRP1 was hypermethylated in RA synovial fibroblasts (RASFs). Next, gain- or loss-of-function experiments were conducted in RASFs to explore the effects of HOTTIP on the biological behaviors of RASFs. Silencing of HOTTIP or overexpression of SFRP1 inhibited RASF proliferation, invasion, and migration, while enhancing apoptosis. The relationship among HOTTIP, SFRP1, and Dnmt3b was determined using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays. The regulatory mechanisms of HOTTIP/Dnmt3b/SFRP1 were explored by altering their expression in RASFs. It was noted that HOTTIP could induce SFRP1 promoter methylation through recruitment of Dnmt3b and activate the Wnt signaling pathway. Finally, a rat RA model was established in order to evaluate the in vivo effects of HOTTIP and SFRP1, which suggested that HOTTIP silencing or SFRP1 elevation inhibited the progression of RA in vivo. Our key findings demonstrate the anti-inflammatory ability of HOTTIP silencing in RA through SFRP1 promoter demethylation. These findings support HOTTIP as a candidate anti-arthritis target.
format Online
Article
Text
id pubmed-6948255
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher American Society of Gene & Cell Therapy
record_format MEDLINE/PubMed
spelling pubmed-69482552020-01-09 Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1 Hu, Xumin Tang, Jianhua Hu, Xuyun Bao, Peng Deng, Weixi Wu, Jionglin Liang, Yuwei Chen, Zhipeng Gao, Liangbin Tang, Yong Mol Ther Nucleic Acids Article Accumulating evidence suggests long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Here, we aimed to define the role of HOXA transcript at the distal tip (HOTTIP) in RA pathogenesis in relation to SFRP1 methylation and Wnt signaling pathway. HOTTIP was found highly expressed, and SFRP1 was hypermethylated in RA synovial fibroblasts (RASFs). Next, gain- or loss-of-function experiments were conducted in RASFs to explore the effects of HOTTIP on the biological behaviors of RASFs. Silencing of HOTTIP or overexpression of SFRP1 inhibited RASF proliferation, invasion, and migration, while enhancing apoptosis. The relationship among HOTTIP, SFRP1, and Dnmt3b was determined using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), RNA pull-down, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays. The regulatory mechanisms of HOTTIP/Dnmt3b/SFRP1 were explored by altering their expression in RASFs. It was noted that HOTTIP could induce SFRP1 promoter methylation through recruitment of Dnmt3b and activate the Wnt signaling pathway. Finally, a rat RA model was established in order to evaluate the in vivo effects of HOTTIP and SFRP1, which suggested that HOTTIP silencing or SFRP1 elevation inhibited the progression of RA in vivo. Our key findings demonstrate the anti-inflammatory ability of HOTTIP silencing in RA through SFRP1 promoter demethylation. These findings support HOTTIP as a candidate anti-arthritis target. American Society of Gene & Cell Therapy 2019-11-26 /pmc/articles/PMC6948255/ /pubmed/31902746 http://dx.doi.org/10.1016/j.omtn.2019.11.015 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hu, Xumin
Tang, Jianhua
Hu, Xuyun
Bao, Peng
Deng, Weixi
Wu, Jionglin
Liang, Yuwei
Chen, Zhipeng
Gao, Liangbin
Tang, Yong
Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1
title Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1
title_full Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1
title_fullStr Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1
title_full_unstemmed Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1
title_short Silencing of Long Non-coding RNA HOTTIP Reduces Inflammation in Rheumatoid Arthritis by Demethylation of SFRP1
title_sort silencing of long non-coding rna hottip reduces inflammation in rheumatoid arthritis by demethylation of sfrp1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948255/
https://www.ncbi.nlm.nih.gov/pubmed/31902746
http://dx.doi.org/10.1016/j.omtn.2019.11.015
work_keys_str_mv AT huxumin silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT tangjianhua silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT huxuyun silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT baopeng silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT dengweixi silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT wujionglin silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT liangyuwei silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT chenzhipeng silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT gaoliangbin silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1
AT tangyong silencingoflongnoncodingrnahottipreducesinflammationinrheumatoidarthritisbydemethylationofsfrp1