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CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression

Genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) most of them located in non-protein coding regions of the genome. One such locus is the CAD Associated Region between MFGE8 and ABHD2 (CARMA), a ∼18 kb haplotype that was recently shown to re...

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Autores principales: Soubeyrand, Sébastien, Nikpay, Majid, Lau, Paulina, Turner, Adam, Hoang, Huy-Dung, Alain, Tommy, McPherson, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311772/
https://www.ncbi.nlm.nih.gov/pubmed/32625236
http://dx.doi.org/10.3389/fgene.2020.00631
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author Soubeyrand, Sébastien
Nikpay, Majid
Lau, Paulina
Turner, Adam
Hoang, Huy-Dung
Alain, Tommy
McPherson, Ruth
author_facet Soubeyrand, Sébastien
Nikpay, Majid
Lau, Paulina
Turner, Adam
Hoang, Huy-Dung
Alain, Tommy
McPherson, Ruth
author_sort Soubeyrand, Sébastien
collection PubMed
description Genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) most of them located in non-protein coding regions of the genome. One such locus is the CAD Associated Region between MFGE8 and ABHD2 (CARMA), a ∼18 kb haplotype that was recently shown to regulate vicinal protein coding genes. Here, we further investigate the region by examining a long non-coding RNA gene locus (CARMAL/RP11-326A19.4/AC013565) abutting the CARMA region. Expression-genotype correlation analyses of public databases indicate that CARMAL levels are influenced by CAD associated variants suggesting that it might have cardioprotective functions. We found CARMAL to be stably expressed at relatively low levels and enriched in the cytosol. CARMAL function was investigated by several gene targeting approaches in HEK293T: inactive CRISPR fusion proteins, antisense, overexpression and inactivation by CRISPR-mediated knock-out. Modest increases in CARMAL (3–4×) obtained via CRISPRa using distinct single-guided RNAs did not result in consistent transcriptome effects. By contrast, CARMAL deletion or reduced CARMAL expression via CRISPRi increased MFGE8 levels, suggesting that CARMAL is contributing to reduce MFGE8 expression under basal conditions. While future investigations are required to clarify the mechanism(s) by which CARMAL acts on MFGE8, integrative bioinformatic analyses of the transcriptome of CARMAL deleted cells suggest that this locus may also be involved in leucine metabolism, splicing, transcriptional regulation and Shwachman-Bodian-Diamond syndrome protein function.
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spelling pubmed-73117722020-07-02 CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression Soubeyrand, Sébastien Nikpay, Majid Lau, Paulina Turner, Adam Hoang, Huy-Dung Alain, Tommy McPherson, Ruth Front Genet Genetics Genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) most of them located in non-protein coding regions of the genome. One such locus is the CAD Associated Region between MFGE8 and ABHD2 (CARMA), a ∼18 kb haplotype that was recently shown to regulate vicinal protein coding genes. Here, we further investigate the region by examining a long non-coding RNA gene locus (CARMAL/RP11-326A19.4/AC013565) abutting the CARMA region. Expression-genotype correlation analyses of public databases indicate that CARMAL levels are influenced by CAD associated variants suggesting that it might have cardioprotective functions. We found CARMAL to be stably expressed at relatively low levels and enriched in the cytosol. CARMAL function was investigated by several gene targeting approaches in HEK293T: inactive CRISPR fusion proteins, antisense, overexpression and inactivation by CRISPR-mediated knock-out. Modest increases in CARMAL (3–4×) obtained via CRISPRa using distinct single-guided RNAs did not result in consistent transcriptome effects. By contrast, CARMAL deletion or reduced CARMAL expression via CRISPRi increased MFGE8 levels, suggesting that CARMAL is contributing to reduce MFGE8 expression under basal conditions. While future investigations are required to clarify the mechanism(s) by which CARMAL acts on MFGE8, integrative bioinformatic analyses of the transcriptome of CARMAL deleted cells suggest that this locus may also be involved in leucine metabolism, splicing, transcriptional regulation and Shwachman-Bodian-Diamond syndrome protein function. Frontiers Media S.A. 2020-06-17 /pmc/articles/PMC7311772/ /pubmed/32625236 http://dx.doi.org/10.3389/fgene.2020.00631 Text en Copyright © 2020 Soubeyrand, Nikpay, Lau, Turner, Hoang, Alain and McPherson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Soubeyrand, Sébastien
Nikpay, Majid
Lau, Paulina
Turner, Adam
Hoang, Huy-Dung
Alain, Tommy
McPherson, Ruth
CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression
title CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression
title_full CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression
title_fullStr CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression
title_full_unstemmed CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression
title_short CARMAL Is a Long Non-coding RNA Locus That Regulates MFGE8 Expression
title_sort carmal is a long non-coding rna locus that regulates mfge8 expression
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311772/
https://www.ncbi.nlm.nih.gov/pubmed/32625236
http://dx.doi.org/10.3389/fgene.2020.00631
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