Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers
- Xabier Agirre1,
- Giancarlo Castellano2,
- Marien Pascual1,
- Simon Heath3,
- Marta Kulis2,
- Victor Segura4,
- Anke Bergmann5,
- Anna Esteve3,
- Angelika Merkel3,
- Emanuele Raineri3,
- Lidia Agueda3,
- Julie Blanc3,
- David Richardson6,
- Laura Clarke6,
- Avik Datta6,
- Nuria Russiñol2,
- Ana C. Queirós2,
- Renée Beekman2,
- Juan R. Rodríguez-Madoz1,
- Edurne San José-Enériz1,
- Fang Fang7,
- Norma C. Gutiérrez8,
- José M. García-Verdugo9,
- Michael I. Robson10,
- Eric C. Schirmer10,
- Elisabeth Guruceaga4,
- Joost H.A. Martens11,
- Marta Gut3,
- Maria J. Calasanz12,
- Paul Flicek6,
- Reiner Siebert5,
- Elías Campo2,
- Jesús F. San Miguel13,
- Ari Melnick7,
- Hendrik G. Stunnenberg11,
- Ivo G. Gut3,
- Felipe Prosper1,13,14 and
- José I. Martín-Subero2,14
- 1Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
- 2Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
- 3Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
- 4Unidad de Bioinformática, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
- 5Institute of Human Genetics, Christian-Albrechts-University, 24105 Kiel, Germany;
- 6European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, CB10 1SD, United Kingdom;
- 7Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
- 8Hospital Universitario de Salamanca, 37007 Salamanca, Spain;
- 9Department of Cellular Morphology, University of Valencia, Unidad Mixta CIPF-UVEG, CIBERNED, 46100 Valencia, Spain;
- 10The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom;
- 11Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands;
- 12Departamento de Genética, Universidad de Navarra, 31008 Pamplona, Spain;
- 13Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain
- Corresponding authors: xaguirre{at}unav.es, fprosper{at}unav.es, imartins{at}clinic.ub.es
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↵14 Senior authors.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.180240.114.
- Received June 20, 2014.
- Accepted January 22, 2015.
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