Scientific publications

Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers

Agirre X (1), Castellano G (2), Pascual M (3), Heath S (4), Kulis M (2), Segura V (5), Bergmann A (6), Esteve A (4), Merkel A (4), Raineri E (4), Agueda L (4), Blanc J (4), Richardson D (7), Clarke L (7), Datta A (7), Russiñol N (2), Queirós AC (2), Beekman R (2), Rodríguez-Madoz JR (3), San José-Enériz E (3), Fang F (8), Gutiérrez NC (9), García-Verdugo JM (10), Robson MI (11), Schirmer EC (11), Guruceaga E (5), Martens JH (12), Gut M (4), Calasanz MJ (13), Flicek P (7), Siebert R (6), Campo E (2), Miguel JF (14), Melnick A (8), Stunnenberg HG (12), Gut IG (4), Prosper F (15), Martín-Subero JI (16).
(1) Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain
(2) Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain;
(3) Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
(4) Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain;
(5) Unidad de Bioinformática, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, 31008 Pamplona, Spain;
(6) Institute of Human Genetics, Christian-Albrechts-University, 24105 Kiel, Germany;
(7) European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, CB10 1SD, United Kingdom;
(8) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA;
(9) Hospital Universitario de Salamanca, 37007 Salamanca, Spain;
(10) Department of Cellular Morphology, University of Valencia, Unidad Mixta CIPF-UVEG, CIBERNED, 46100 Valencia, Spain;
(11) The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom;
(12) Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands;
(13) Departamento de Genética, Universidad de Navarra, 31008 Pamplona, Spain;
(14) Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain.
(15) 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
(16) Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain

Magazine: Genome Research

Date: Apr 1, 2015

Cell Therapy Area [SP] Haematology and Hameotherapy

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.

CITATION  Genome Res. 2015 Apr;25(4):478-87. doi: 10.1101/gr.180240.114. Epub 2015 Feb 2

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