title: The DNA methylation drift of the atherosclerotic aorta increases with lesion progression.
abstract: BACKGROUND
  Atherosclerosis severity-independent alterations in DNA methylation, a reversible and highly regulated DNA modification, have been detected in aortic atheromas, thus supporting the hypothesis that epigenetic mechanisms participate in the pathogenesis of atherosclerosis. One yet unaddressed issue is whether the progression of atherosclerosis is associated with an increase in DNA methylation drift in the vascular tissue. The purpose of the study was to identify CpG methylation profiles that vary with the progression of atherosclerosis in the human aorta.
  
  
  METHODS
  We interrogated a set of donor-matched atherosclerotic and normal aortic samples ranging from histological grade III to VII, with a high-density (>450,000 CpG sites) DNA methylation microarray.
  
  
  RESULTS
  We detected a correlation between histological grade and intra-pair differential methylation for 1,985 autosomal CpGs, the vast majority of which drifted towards hypermethylation with lesion progression. The identified CpG loci map to genes that are regulated by known critical transcription factors involved in atherosclerosis and participate in inflammatory and immune responses. Functional relevance was corroborated by crossing the DNA methylation profiles with expression data obtained in the same human aorta sample set, by a transcriptome-wide analysis of murine atherosclerotic aortas and from available public databases.
  
  
  CONCLUSIONS
  Our work identifies for the first time atherosclerosis progression-specific DNA methylation profiles in the vascular tissue. These findings provide potential novel markers of lesion severity and targets to counteract the progression of the atheroma.
authors.affiliation: Department of Genetic Engineering, CINVESTAV, Irapuato, Guanajuato, Mexico. pilarica03@gmail.com.
authors.forename: María del Pilar
authors.initials: Mdel P
authors.lastname: Valencia-Morales
authors.affiliation: Department of Medical Sciences, Division of Health Sciences, León Campus, University of Guanajuato, 20 de Enero no. 929, 37320, León, Guanajuato, Mexico. szaina@ugto.mx.|Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. szaina@ugto.mx.
authors.forename: Silvio
authors.initials: S
authors.lastname: Zaina
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. hheyn@idibell.cat.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. fjcarmona@idibell.cat.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. varolnur@gmail.com.
authors.forename: Nuray
authors.initials: N
authors.lastname: Varol
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. s.sayolspuig@imb-mainz.de.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.affiliation: Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain. ecm@bellvitgehospital.cat.|Department of Pathology and Experimental Therapeutics, University of Barcelona, Barcelona, Catalonia, Spain. ecm@bellvitgehospital.cat.
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.affiliation: Department of Anatomic Pathology, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain. jramirez@clinic.ub.es.
authors.forename: José
authors.initials: J
authors.lastname: Ramírez-Ruz
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. agomezm@idibell.cat.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. smoran@idibell.cat.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Department of Genetic Engineering, CINVESTAV, Irapuato, Guanajuato, Mexico. glund@ira.cinvestav.mx.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Lund
authors.affiliation: Department of Genetic Engineering, CINVESTAV, Irapuato, Guanajuato, Mexico. drodrigu@ira.cinvestav.mx.
authors.forename: Dalia
authors.initials: D
authors.lastname: Rodríguez-Ríos
authors.affiliation: Bachelor's Degree in Nutrition Programme, Division of Health Sciences, León Campus, University of Guanajuato, León, Guanajuato, Mexico. glg_2025@hotmail.com.
authors.forename: Gladys
authors.initials: G
authors.lastname: López-González
authors.affiliation: Bachelor's Degree in Nutrition Programme, Division of Health Sciences, León Campus, University of Guanajuato, León, Guanajuato, Mexico. magda.mrna@gmail.com.
authors.forename: Magda
authors.initials: M
authors.lastname: Ramírez-Nava
authors.affiliation: Department of Genetic Engineering, CINVESTAV, Irapuato, Guanajuato, Mexico. crocha@ira.cinvestav.mx.
authors.forename: Carmen
authors.initials: C
authors.lastname: de la Rocha
authors.affiliation: University DNA Massive Sequencing Unit, Institute of Biotechnology, UNAM, Cuernavaca, Morelos, Mexico. alexsf@ibt.unam.mx.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sanchez-Flores
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Av. Gran Vía s/n km. 2.7, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. mesteller@idibell.cat.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain. mesteller@idibell.cat.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Catalonia, Spain. mesteller@idibell.cat.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology*; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology*; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D030541:Databases, Genetic; D018450:Disease Progression; D044127:Epigenesis, Genetic; D006801:Humans; D007107:Immune System; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D058226:Plaque, Atherosclerotic / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors