Loci cg06256735 and cg15815843 in the MFAP5 gene regulatory regions are hypomethylated in varicose veins apparently due to active demethylation

Author:

Smetanina Mariya A.12ORCID,Korolenya Valeria A.13,Sipin Fedor A.13,Oscorbin Igor P.1,Sevostyanova Kseniya S.45,Gavrilov Konstantin A.45,Shevela Andrey I.45,Filipenko Maxim L.1

Affiliation:

1. 1Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine (ICBFM), Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia

2. 2Department of Fundamental Medicine, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University (NSU), Novosibirsk 630090, Russia

3. 3Department of Natural Sciences, Novosibirsk State University (NSU), Novosibirsk 630090, Russia

4. 4Center of New Medical Technologies, Institute of Chemical Biology and Fundamental Medicine (ICBFM), Siberian Branch of the Russian Academy of Sciences (SB RAS), Novosibirsk 630090, Russia

5. 5Department of Surgical Diseases, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University (NSU), Novosibirsk 630090, Russia

Abstract

Abstract Varicose vein disease (VVD) is a common health problem worldwide. Microfibril-associated protein 5 (MFAP5) is one of the potential key players in its pathogenesis. Our previous microarray analysis revealed the cg06256735 and cg15815843 loci in the regulatory regions of the MFAP5 gene as hypomethylated in varicose veins which correlated with its up-regulation. The aim of this work was to validate preliminary microarray data, estimate the level of 5-hydroxymethylcytosine (5hmC) at these loci, and determine the methylation status of one of them in different layers of the venous wall. For this, methyl- and hydroxymethyl-sensitive restriction techniques were used followed by real-time PCR and droplet digital PCR, correspondingly, as well as bisulfite pyrosequencing of +/- oxidized DNA. Our microarray data on hypomethylation at the cg06256735 and cg15815843 loci in whole varicose vein segments were confirmed and it was also demonstrated that the level of 5hmC at these loci is increased in VVD. Specifically, among other layers of the venous wall, tunica (t.) intima is the main contributor to hypomethylation at the cg06256735 locus in varicose veins. Thus, it was shown that hypomethylation at the cg06256735 and cg15815843 loci takes place in VVD, with evidence to suggest that it happens through their active demethylation leading to up-regulation of the MFAP5 gene, and t. intima is most involved in this biochemical process.

Funder

Program of Fundamental Scientific Research of the Russian Federation (PFSR RF) “Fundamental Basics of Health Preservation”

Russian Science Foundation

Publisher

Portland Press Ltd.

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