title: Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers.
abstract: While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.
authors: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain; xaguirre@unav.es fprosper@unav.es imartins@clinic.ub.es.
authors: Xabier
authors: X
authors: Agirre
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
authors: Giancarlo
authors: G
authors: Castellano
authors: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
authors: Marien
authors: M
authors: Pascual
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Simon
authors: S
authors: Heath
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
authors: Marta
authors: M
authors: Kulis
authors: Unidad de Bioinformática, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
authors: Victor
authors: V
authors: Segura
authors: Institute of Human Genetics, Christian-Albrechts-University, 24105 Kiel, Germany;
authors: Anke
authors: A
authors: Bergmann
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Anna
authors: A
authors: Esteve
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Angelika
authors: A
authors: Merkel
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Emanuele
authors: E
authors: Raineri
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Lidia
authors: L
authors: Agueda
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Julie
authors: J
authors: Blanc
authors: European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, CB10 1SD, United Kingdom;
authors: David
authors: D
authors: Richardson
authors: European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, CB10 1SD, United Kingdom;
authors: Laura
authors: L
authors: Clarke
authors: European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, CB10 1SD, United Kingdom;
authors: Avik
authors: A
authors: Datta
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
authors: Nuria
authors: N
authors: Russiñol
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
authors: Ana C
authors: AC
authors: Queirós
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
authors: Renée
authors: R
authors: Beekman
authors: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
authors: Juan R
authors: JR
authors: Rodríguez-Madoz
authors: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
authors: Edurne
authors: E
authors: San José-Enériz
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
authors: Fang
authors: F
authors: Fang
authors: Hospital Universitario de Salamanca, 37007 Salamanca, Spain;
authors: Norma C
authors: NC
authors: Gutiérrez
authors: Department of Cellular Morphology, University of Valencia, Unidad Mixta CIPF-UVEG, CIBERNED, 46100 Valencia, Spain;
authors: José M
authors: JM
authors: García-Verdugo
authors: The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom;
authors: Michael I
authors: MI
authors: Robson
authors: The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom;
authors: Eric C
authors: EC
authors: Schirmer
authors: Unidad de Bioinformática, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
authors: Elisabeth
authors: E
authors: Guruceaga
authors: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands;
authors: Joost H A
authors: JH
authors: Martens
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Marta
authors: M
authors: Gut
authors: Departamento de Genética, Universidad de Navarra, 31008 Pamplona, Spain;
authors: Maria J
authors: MJ
authors: Calasanz
authors: European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, CB10 1SD, United Kingdom;
authors: Paul
authors: P
authors: Flicek
authors: Institute of Human Genetics, Christian-Albrechts-University, 24105 Kiel, Germany;
authors: Reiner
authors: R
authors: Siebert
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
authors: Elías
authors: E
authors: Campo
authors: Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain.
authors: Jesús F San
authors: JF
authors: Miguel
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
authors: Ari
authors: A
authors: Melnick
authors: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands;
authors: Hendrik G
authors: HG
authors: Stunnenberg
authors: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
authors: Ivo G
authors: IG
authors: Gut
authors: Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain; Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain xaguirre@unav.es fprosper@unav.es imartins@clinic.ub.es.
authors: Felipe
authors: F
authors: Prosper
authors: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; xaguirre@unav.es fprosper@unav.es imartins@clinic.ub.es.
authors: José I
authors: JI
authors: Martín-Subero
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010950:Plasma Cells / Q000166:cytology*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D014157:Transcription Factors
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