title: The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells.
abstract: Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Jordà
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Díez-Villanueva
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Mallona
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Martín
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Lois
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Barrera
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08908, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona 08907, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Josep Carreras Leukaemia Research Institute (IJC), Badalona 08916, Catalonia, Spain.
authors.forename: Tanya
authors.initials: T
authors.lastname: Vavouri
authors.affiliation: Germans Trias i Pujol Health Science Research Institute (IGTP), Badalona 08916, Catalonia, Spain.|Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona 08916, Catalonia, Spain.
authors.forename: Miguel A
authors.identifier: 0000-0002-4090-793X
authors.initials: MA
authors.lastname: Peinado
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans