Silvio Zaina1, Isabel Gonçalves2, F Javier Carmona2, Antonio Gomez2, Holger Heyn2, Inês G Mollet2, Sebastian Moran2, Nuray Varol2, Manel Esteller1. 1. From the Division of Health Sciences, Department of Medical Sciences, León Campus, University of Guanajuato, León, Gto., Mexico (S.Z.); Experimental Cardiovascular Research and Department of Cardiology, Clinical Sciences Malmö, Lund University, Sweden (I.G.); Department of Clinical Sciences, Lund University, Malmö, Sweden (I.G.M.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain (F.J.C., A.G., H.H., S.M., N.V., M.E., S.Z.); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (M.E.); 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, León Campus, University of Guanajuato, León, Gto., Mexico (S.Z.); Experimental Cardiovascular Research and Department of Cardiology, Clinical Sciences Malmö, Lund University, Sweden (I.G.); Department of Clinical Sciences, Lund University, Malmö, Sweden (I.G.M.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain (F.J.C., A.G., H.H., S.M., N.V., M.E., S.Z.); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (M.E.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
Abstract
OBJECTIVE: To understand whether cerebrovascular events, a major complication of atherosclerosis, are associated with any specific DNA methylation changes in the carotid plaque. APPROACH AND RESULTS: We profiled the DNA methylomes of human symptomatic carotid plaques obtained from patients who had cerebrovascular events (n=19) and asymptomatic counterparts (n=19) with a high-density microarray (≈485 000 CpG sites, Illumina), and crossed DNA methylation data with RNAseq-based expression data from an independent symptomatic carotid plaque set (n=8). Few (30) CpGs showed a significant (P<0.05; absolute Delta-Beta, >0.20) differential methylation between the 2 groups. Within symptomatic carotid plaques, DNA methylation correlated significantly with postcerebrovascular event time (range, 3-45 days; r-value range, -0.926 to 0.857; P<0.05) for ≈45 000 CpGs, the vast majority of which became hypomethylated with increasing postcerebrovascular event time. Hypomethylation was not due to erasure of the gene-body and CG-poor region hypermethylation that accompany the progression of stable lesions, but rather targeted promoters and CpG islands. Noticeably, promoter hypomethylation and increased expression of genes involved in the inhibition of the inflammatory response, defense against oxidative stress, and active DNA demethylation were observed with increasing postcerebrovascular event time. Concomitantly, histological changes consistent with phagocyte-driven plaque healing were observed. CONCLUSIONS: Weak changes in the DNA methylome distinguish symptomatic from asymptomatic plaques, but a widespread demethylation resulting in permissive transcriptional marks at atheroprotective gene promoters is established in plaques after a cerebrovascular event, thus mirroring previous observations that ruptured plaques tend to revert to a stable structure. The identified loci are candidate targets to accelerate the pace of carotid plaque stabilization.
OBJECTIVE: To understand whether cerebrovascular events, a major complication of atherosclerosis, are associated with any specific DNA methylation changes in the carotid plaque. APPROACH AND RESULTS: We profiled the DNA methylomes of human symptomatic carotid plaques obtained from patients who had cerebrovascular events (n=19) and asymptomatic counterparts (n=19) with a high-density microarray (≈485 000 CpG sites, Illumina), and crossed DNA methylation data with RNAseq-based expression data from an independent symptomatic carotid plaque set (n=8). Few (30) CpGs showed a significant (P<0.05; absolute Delta-Beta, >0.20) differential methylation between the 2 groups. Within symptomatic carotid plaques, DNA methylation correlated significantly with postcerebrovascular event time (range, 3-45 days; r-value range, -0.926 to 0.857; P<0.05) for ≈45 000 CpGs, the vast majority of which became hypomethylated with increasing postcerebrovascular event time. Hypomethylation was not due to erasure of the gene-body and CG-poor region hypermethylation that accompany the progression of stable lesions, but rather targeted promoters and CpG islands. Noticeably, promoter hypomethylation and increased expression of genes involved in the inhibition of the inflammatory response, defense against oxidative stress, and active DNA demethylation were observed with increasing postcerebrovascular event time. Concomitantly, histological changes consistent with phagocyte-driven plaque healing were observed. CONCLUSIONS: Weak changes in the DNA methylome distinguish symptomatic from asymptomatic plaques, but a widespread demethylation resulting in permissive transcriptional marks at atheroprotective gene promoters is established in plaques after a cerebrovascular event, thus mirroring previous observations that ruptured plaques tend to revert to a stable structure. The identified loci are candidate targets to accelerate the pace of carotid plaque stabilization.
Authors: Angela L Riffo-Campos; Azahara Fuentes-Trillo; Wan Y Tang; Zoraida Soriano; Griselda De Marco; Pilar Rentero-Garrido; Victoria Adam-Felici; Veronica Lendinez-Tortajada; Kevin Francesconi; Walter Goessler; Christine Ladd-Acosta; Montse Leon-Latre; Jose A Casasnovas; F Javier Chaves; Ana Navas-Acien; Eliseo Guallar; Maria Tellez-Plaza Journal: Philos Trans R Soc Lond B Biol Sci Date: 2018-06-05 Impact factor: 6.237
Authors: Fabiola E Tristán-Flores; Plinio Guzmán; Melany S Ortega-Kermedy; Gabriela Cruz-Torres; Carmen de la Rocha; Guillermo A Silva-Martínez; Dalia Rodríguez-Ríos; Yolanda Alvarado-Caudillo; Gloria Barbosa-Sabanero; Sergi Sayols; Gertrud Lund; Silvio Zaina Journal: J Am Heart Assoc Date: 2018-01-31 Impact factor: 5.501