Einari Aavik1, Henri Lumivuori1, Olli Leppänen2, Thomas Wirth1, Sanna-Kaisa Häkkinen1, Jan-Hinrich Bräsen3, Ulrich Beschorner4, Thomas Zeller4, Maarten Braspenning5, Wim van Criekinge6, Kimmo Mäkinen7, Seppo Ylä-Herttuala8. 1. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, Kuopio, University of Eastern Finland, PO Box 1627 (Neulaniementie 2), Kuopio, FIN-70211, Finland. 2. Centre for R&D, Uppsala University/County Council of Gävleborg, Gävle, Sweden. 3. Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany. 4. Department of Angiology, Universitäts-Herzzentrum Freiburg Bad Krozingen, Bad Krozingen, Germany. 5. NXT-Dx, Ghent, Belgium. 6. Laboratory for Bioinformatics and Computational Genomics, Ghent University, Ghent, Belgium. 7. Vascular Surgery Unit, Kuopio University Hospital, Kuopio, Finland. 8. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, Kuopio, University of Eastern Finland, PO Box 1627 (Neulaniementie 2), Kuopio, FIN-70211, Finland Science Service Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland seppo.ylaherttuala@uef.fi.
Abstract
AIMS: We conducted a genome-wide analysis to identify differentially methylated genes in atherosclerotic lesions. METHODS: DNA methylation at promoters, exons and introns was identified by massive parallel sequencing. Gene expression was analysed by microarrays, qPCR, immunohistochemistry and western blots. RESULTS: Globally, hypomethylation of chromosomal DNA predominates in atherosclerotic plaques and two-thirds of genes showing over 2.5-fold differential in DNA methylation are up-regulated in comparison to healthy mammary arteries. The imprinted chromatin locus 14q32 was identified for the first time as an extensively hypomethylated area in atherosclerosis with highly induced expression of miR127, -136, -410, -431, -432, -433 and capillary formation-associated gene RTL1. The top 100 list of hypomethylated promoters exhibited over 1000-fold enrichment for miRNAs, many of which mapped to locus 14q32. Unexpectedly, also gene body hypermethylation was found to correlate with stimulated mRNA expression. CONCLUSION: Significant changes in genomic methylation were identified in atherosclerotic lesions. The most prominent gene cluster activated via hypomethylation was detected at imprinted chromosomal locus 14q32 with several clustered miRNAs that were up-regulated. These results suggest that epigenetic changes are involved in atherogenesis and may offer new potential therapeutic targets for vascular diseases. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: We conducted a genome-wide analysis to identify differentially methylated genes in atherosclerotic lesions. METHODS: DNA methylation at promoters, exons and introns was identified by massive parallel sequencing. Gene expression was analysed by microarrays, qPCR, immunohistochemistry and western blots. RESULTS: Globally, hypomethylation of chromosomal DNA predominates in atherosclerotic plaques and two-thirds of genes showing over 2.5-fold differential in DNA methylation are up-regulated in comparison to healthy mammary arteries. The imprinted chromatin locus 14q32 was identified for the first time as an extensively hypomethylated area in atherosclerosis with highly induced expression of miR127, -136, -410, -431, -432, -433 and capillary formation-associated gene RTL1. The top 100 list of hypomethylated promoters exhibited over 1000-fold enrichment for miRNAs, many of which mapped to locus 14q32. Unexpectedly, also gene body hypermethylation was found to correlate with stimulated mRNA expression. CONCLUSION: Significant changes in genomic methylation were identified in atherosclerotic lesions. The most prominent gene cluster activated via hypomethylation was detected at imprinted chromosomal locus 14q32 with several clustered miRNAs that were up-regulated. These results suggest that epigenetic changes are involved in atherogenesis and may offer new potential therapeutic targets for vascular diseases. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Gregory Stone; Ashley Choi; Oliva Meritxell; Joshua Gorham; Mahyar Heydarpour; Christine E Seidman; Jon G Seidman; Sary F Aranki; Simon C Body; Vincent J Carey; Benjamin A Raby; Barbara E Stranger; Jochen D Muehlschlegel Journal: Hum Mol Genet Date: 2019-05-15 Impact factor: 6.150