Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease

Bibliographic Details
Main Author:	Cho, Hyosuk
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2021
Subjects:	Genetics
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1602176156319058

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case16021761563190582021-08-03T07:16:22Z Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease Cho, Hyosuk Genetics Coronary artery disease (CAD) is the leading cause of death worldwide. CAD is caused by atherosclerosis in the coronary arteries, and genetic factors are critical to the development of CAD. Although genome-wide association studies emphasized the importance of 9p21.3 locus as the first and most robust locus of CAD, the causal genes at this locus and their molecular mechanisms remain to be identified. In our studies with the long non-coding RNA gene, ANRIL, located within the 9p21.3 locus, we focused on the trafficking of monocytes across the endothelium, the critical cellular processes of CAD.First, we highlight our key findings that overexpression of the most abundant transcript of ANRIL, DQ485454, significantly reduces the trafficking of monocytes. In contrast, siRNA-mediated ANRIL knockdown (KD) has the opposite effect by modulating the expression levels of CLIP1, EZR, and LYVE1. Although microarray and follow-up quantitative RT-PCR analyses revealed multiple downstream genes of ANRIL, our mechanistic studies demonstrated that overexpression of CLIP1, EZR, and LYVE1 reversed the effects of ANRIL KD on trafficking of monocytes.Next, we further describe our discovery that ANRIL KD upregulates the expression of TMEM106B genes. Mechanistic studies disclosed that KD of TMEM106B reversed the effects of ANRIL KD on monocyte trafficking. Furthermore, the decreased trafficking of monocytes induced by ANRIL overexpression was fully reversed by overexpressing TMEM106B, which shows that TMEM106B is a necessary player in changing the cell processes that lead to CAD. Interestingly, we found that genomic variants in TMEM106B are highly associated with CAD, and significant gene-gene interaction was detected between rs2383207 in ANRIL and rs3807865 in TMEM106B, which suggests that ANRIL regulates EC functions by modulating TMEM106B expression.We further report that the two major splice variants of ANRIL, DQ485454 and NR_003529, demonstrate antagonizing effects on the endothelial cell activities associated with CAD. Modulating the expression level of the transcripts in the opposite direction maximized the observed changes in cellular activities we acquired in the previous studies. The transcripts also demonstrated expression regulation of the key downstream genes of ANRIL in the opposite direction.Altogether, these data suggest that ANRIL is the causal gene for CAD at the 9p21.3 locus that regulates EC functions directly related to CAD, and provide in vitro evidence that splice variants of ANRIL are the essential components of the gene in modulating the CAD risk by regulating the expression of the downstream genes, CLIP1, EZR, LYVE1, and TMEM106B. 2021-01-22 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1602176156319058 http://rave.ohiolink.edu/etdc/view?acc_num=case1602176156319058 restricted--full text unavailable until 2022-01-15 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Genetics
spellingShingle	Genetics Cho, Hyosuk Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease
author	Cho, Hyosuk
author_facet	Cho, Hyosuk
author_sort	Cho, Hyosuk
title	Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease
title_short	Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease
title_full	Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease
title_fullStr	Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease
title_full_unstemmed	Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease
title_sort	elucidating the roles and mechanisms by which a long non-coding rna, anril, regulates endothelial cell activities in the development of coronary artery disease
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2021
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1602176156319058
work_keys_str_mv	AT chohyosuk elucidatingtherolesandmechanismsbywhichalongnoncodingrnaanrilregulatesendothelialcellactivitiesinthedevelopmentofcoronaryarterydisease
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Elucidating the Roles and Mechanisms by which a Long Non-coding RNA, ANRIL, Regulates Endothelial Cell Activities in the Development of Coronary Artery Disease

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