DNA Methylation and Gene Expression Profiling Reveal MFAP5 as a Regulatory Driver of Extracellular Matrix Remodeling in Varicose Vein Disease

Abstract

Aim: To integrate transcriptomic and DNA-methylomic measurements on varicose versus normal veins using a systems biological analysis to shed light on the interplay between genetic and epigenetic factors. Materials & methods: Differential expression and methylation were measured using microarrays, supported by real-time quantitative PCR and immunohistochemistry confirmation for relevant gene products. A systems biological ‘upstream analysis’ was further applied. Results: We identified several potential key players contributing to extracellular matrix remodeling in varicose veins. Specifically, our analysis suggests MFAP5 acting as a master regulator, upstream of integrins, of the cellular network affecting the varicose vein condition. Possible mechanism and pathogenic model were outlined. Conclusion: A coherent model proposed incorporates the relevant signaling networks and will hopefully aid further studies on varicose vein pathogenesis.

Keywords::

• DNA methylation
• extracellular matrix
• gene expression
• MFAP5
• systems biological analysis
• varicose vein(s)
• vascular remodeling

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/doi/suppl/10.4155/epi-2018-0001

Data deposition

Raw and normalized data were submitted to Gene Expression Omnibus (GEO: GSE68309 – Genome-wide gene expression profiles of 14 paired [normal and varicose] vein samples from the patients with varicose vein disease; GEO: GSE68319 – Genome-wide DNA methylation profiles of 20 paired [normal and varicose] vein samples from the patients with varicose vein disease).

Acknowledgements

The authors are grateful to E Wingender (Institute of Bioinformatics, University Medical Center Göttingen, Georg August University and geneXplain GmbH, Germany) for critical reading and corrections of the manuscript. They are also thankful to the native English speakers J Baker (University of Sydney, Australia) and H Jacob (Texas A&M University, USA) for editing assistance and thorough text revision.

Financial & competing interests disclosure

This work was supported by the Russian Science Foundation (grant number 17-75-20223) (including sample collection and gene expression validations by real-time quantitative PCR). Microarray and immunohistochemistry experiments and bioinformatics data analysis were supported by the SB RAS Complex scientific program II.2П/VI.62-5 ‘Molecular and Cellular Biology’ (grant number 0309-2015-0028). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Institutional Review Board of the Institute of Chemical Biology and Fundamental Medicine (protocol No.15, 13 September 2013) and the Pirogov Russian National Research Medical University (protocol No.123, 21 January 2013). The study was conducted in accordance with the principles written in the Declaration of Helsinki. Written informed consent was obtained from all patients before their surgeries, who willingly agreed to participate in our investigations.

Additional information

Funding

This work was supported by the Russian Science Foundation (grant number 17-75-20223) (including sample collection and gene expression validations by real-time quantitative PCR). Microarray and immunohistochemistry experiments and bioinformatics data analysis were supported by the SB RAS Complex scientific program II.2П/VI.62-5 ‘Molecular and Cellular Biology’ (grant number 0309-2015-0028). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.