title: Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer.
abstract: BACKGROUND
  One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized.
  
  
  RESULTS
  Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis.
  
  
  CONCLUSIONS
  We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 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), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. evidalo@idibell.cat.
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. hferreira@idibell.cat.
authors.forename: Humberto J
authors.initials: HJ
authors.lastname: Ferreira
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. mvizoso@idibell.cat.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vizoso
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. S.SayolsPuig@imb-mainz.de.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. antgomo@gmail.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. smoran@idibell.cat.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. rboque@idibell.cat.
authors.forename: Raquel
authors.initials: R
authors.lastname: Boque-Sastre
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. sguil@idibell.cat.
authors.forename: Sonia
authors.initials: S
authors.lastname: Guil
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. amartinezc@idibell.cat.
authors.forename: Anna
authors.initials: A
authors.lastname: Martinez-Cardus
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA. charles_lin@dfci.harvard.edu.|Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. charles_lin@dfci.harvard.edu.|Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA, 02115, USA. charles_lin@dfci.harvard.edu.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Program in Computational Biology, Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. rroyo@bsc.es.
authors.forename: Romina
authors.initials: R
authors.lastname: Royo
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. jose.sanchezmut@epfl.ch.
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sanchez-Mut
authors.affiliation: Department of Neurosurgery, University of Goettingen, Robert Koch. Str. 40, 37075, Goettingen, Germany. ramon.martinez@med.uni-goettingen.de.
authors.forename: Ramon
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Centre Nacional d'Anàlisi Genòmica, Barcelona, Catalonia, Spain. marta.gut@cnag.crg.eu.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Program in Computational Biology, Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. david.torrents@bsc.es.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Catalonia, Spain. david.torrents@bsc.es.
authors.forename: David
authors.initials: D
authors.lastname: Torrents
authors.affiliation: Joint Biomedical Research Institute-Barcelona Supercomputing Center (IRB-BSC) Program in Computational Biology, Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. modesto.orozco@irbbarcelona.org.|Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10-12, 08028, Barcelona, Catalonia, Spain. modesto.orozco@irbbarcelona.org.|Department of Biochemistry and Molecular Biology, University of Barcelona, 08028, Barcelona, Catalonia, Spain. modesto.orozco@irbbarcelona.org.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.affiliation: Centre Nacional d'Anàlisi Genòmica, Barcelona, Catalonia, Spain. ivo.gut@cnag.crg.eu.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142, USA. young@wi.mit.edu.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. young@wi.mit.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. mesteller@idibell.cat.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Catalonia, Spain. mesteller@idibell.cat.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036, Barcelona, Catalonia, Spain. mesteller@idibell.cat.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic
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