Silvio Zaina1, Holger Heyn2, F Javier Carmona2, Nuray Varol2, Sergi Sayols2, Enric Condom2, José Ramírez-Ruz2, Antonio Gomez2, Isabel Gonçalves2, Sebastian Moran2, Manel Esteller1. 1. From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.). mesteller@idibell.cat szaina@ugto.mx. 2. From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
Abstract
BACKGROUND: Epigenetic alterations may contribute to the development of atherosclerosis. In particular, DNA methylation, a reversible and highly regulated DNA modification, could influence disease onset and progression because it functions as an effector for environmental influences, including diet and lifestyle, both of which are risk factors for cardiovascular diseases. METHODS AND RESULTS: To address the role of DNA methylation changes in atherosclerosis, we compared a donor-matched healthy and atherosclerotic human aorta sample using whole-genome shotgun bisulfite sequencing. We observed that the atherosclerotic portion of the aorta was hypermethylated across many genomic loci in comparison with the matched healthy counterpart. Furthermore, we defined specific loci of differential DNA methylation using a set of donor-matched aortic samples and a high-density (>450 000 CpG sites) DNA methylation microarray. The functional importance in the disease was corroborated by crossing the DNA methylation signature with the corresponding expression data of the same samples. Among the differentially methylated CpGs associated with atherosclerosis onset, we identified genes participating in endothelial and smooth muscle functions. These findings provide new clues toward a better understanding of the molecular mechanisms of atherosclerosis. CONCLUSIONS: Our data identify an atherosclerosis-specific DNA methylation profile that highlights the contribution of different genes and pathways to the disorder. Interestingly, the observed gain of DNA methylation in the atherosclerotic lesions justifies efforts to develop DNA demethylating agents for therapeutic benefit.
BACKGROUND: Epigenetic alterations may contribute to the development of atherosclerosis. In particular, DNA methylation, a reversible and highly regulated DNA modification, could influence disease onset and progression because it functions as an effector for environmental influences, including diet and lifestyle, both of which are risk factors for cardiovascular diseases. METHODS AND RESULTS: To address the role of DNA methylation changes in atherosclerosis, we compared a donor-matched healthy and atherosclerotichuman aorta sample using whole-genome shotgun bisulfite sequencing. We observed that the atherosclerotic portion of the aorta was hypermethylated across many genomic loci in comparison with the matched healthy counterpart. Furthermore, we defined specific loci of differential DNA methylation using a set of donor-matched aortic samples and a high-density (>450 000 CpG sites) DNA methylation microarray. The functional importance in the disease was corroborated by crossing the DNA methylation signature with the corresponding expression data of the same samples. Among the differentially methylated CpGs associated with atherosclerosis onset, we identified genes participating in endothelial and smooth muscle functions. These findings provide new clues toward a better understanding of the molecular mechanisms of atherosclerosis. CONCLUSIONS: Our data identify an atherosclerosis-specific DNA methylation profile that highlights the contribution of different genes and pathways to the disorder. Interestingly, the observed gain of DNA methylation in the atherosclerotic lesions justifies efforts to develop DNA demethylating agents for therapeutic benefit.
Authors: Danielle L Shepherd; Quincy A Hathaway; Mark V Pinti; Cody E Nichols; Andrya J Durr; Shruthi Sreekumar; Kristen M Hughes; Seth M Stine; Ivan Martinez; John M Hollander Journal: J Mol Cell Cardiol Date: 2017-07-11 Impact factor: 5.000
Authors: Guillermo A Silva-Martínez; Dalia Rodríguez-Ríos; Yolanda Alvarado-Caudillo; Alejandro Vaquero; Manel Esteller; F Javier Carmona; Sebastian Moran; Finn C Nielsen; Marie Wickström-Lindholm; Katarzyna Wrobel; Kazimierz Wrobel; Gloria Barbosa-Sabanero; Silvio Zaina; Gertrud Lund Journal: Epigenetics Date: 2016-04-18 Impact factor: 4.528