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TBX5-AS1:2 的高甲基化下调：法洛四联症中长链非编码 RNA 的负调控通过降低 TBX5 表达抑制细胞增殖。

Hypermethylation-mediated down-regulation of lncRNA TBX5-AS1:2 in Tetralogy of Fallot inhibits cell proliferation by reducing TBX5 expression.

机构信息

Department of Facial Plastic and Reconstructive Surgery, ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, China.

Department of Biochemistry and Molecular Biology, Research Center for Birth Defects, Institutes of Biomedical Sciences, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China.

出版信息

J Cell Mol Med. 2020 Jun;24(11):6472-6484. doi: 10.1111/jcmm.15298. Epub 2020 May 5.

DOI:10.1111/jcmm.15298
PMID:32368852
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7294119/
Abstract

Tetralogy of Fallot (TOF) is the most common complex congenital heart disease (CHD) with uncertain cause. Although long non-coding RNAs (lncRNAs) have been implicated in heart development and several CHDs, their role in TOF is not well understood. This study aimed to investigate how dysregulated lncRNAs contribute to TOF. Using Gene Expression Omnibus data mining, bioinformatics analysis and clinical heart tissue sample detecting, we identified a novel antisense lncRNA TBX5-AS1:2 with unknown function that was significantly down-regulated in injured cardiac tissues from TOF patients. LncRNA TBX5-AS1:2 was mainly located in the nucleus of the human embryonic kidney 293 (HEK293T) cells and formed an RNA-RNA double-stranded structure in the overlapping region with its sense mRNA T-box transcription factor 5 (TBX5), which is an important regulator in heart development. Knock-down of lncRNA TBX5-AS1:2 via promoter hypermethylation reduced TBX5 expression at both the mRNA and protein levels by affecting its mRNA stability through RNA-RNA interaction. Moreover, lncRNA TBX5-AS1:2 knock-down inhibited the proliferation of HEK293T cells. In conclusion, these results indicated that lncRNA TBX5-AS1:2 may be involved in TOF by affecting cell proliferation by targeting TBX5.

摘要

法洛四联症（TOF）是最常见的复杂先天性心脏病（CHD），其病因尚不确定。尽管长链非编码 RNA（lncRNA）已被涉及到心脏发育和几种 CHD 中，但它们在 TOF 中的作用尚不清楚。本研究旨在探讨失调的 lncRNA 如何导致 TOF。通过基因表达综合数据库数据挖掘、生物信息学分析和临床心脏组织样本检测，我们鉴定出一种新型反义 lncRNA TBX5-AS1:2，其在 TOF 患者的损伤心脏组织中表达显著下调，但功能未知。lncRNA TBX5-AS1:2 主要位于人胚肾 293（HEK293T）细胞的核内，并在与其有义 mRNA T 框转录因子 5（TBX5）重叠的区域形成 RNA-RNA 双链结构，TBX5 是心脏发育的重要调节因子。通过启动子超甲基化使 lncRNA TBX5-AS1:2 下调，通过 RNA-RNA 相互作用影响其 mRNA 稳定性，从而降低 TBX5 在 mRNA 和蛋白水平的表达。此外，lncRNA TBX5-AS1:2 下调抑制了 HEK293T 细胞的增殖。总之，这些结果表明，lncRNA TBX5-AS1:2 可能通过靶向 TBX5 影响细胞增殖而参与 TOF 的发生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/dd9148491c04/JCMM-24-6472-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/29405287bcdc/JCMM-24-6472-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/5a7c99ec486c/JCMM-24-6472-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/604cffb5bede/JCMM-24-6472-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/dd9148491c04/JCMM-24-6472-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/29405287bcdc/JCMM-24-6472-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/5a7c99ec486c/JCMM-24-6472-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/604cffb5bede/JCMM-24-6472-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d493/7294119/dd9148491c04/JCMM-24-6472-g004.jpg

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