TitleWhole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers.
Publication TypeJournal Article
Year of Publication2015
AuthorsAgirre, Xabier, Castellano Giancarlo, Pascual Marien, Heath Simon, Kulis Marta, Segura Victor, Bergmann Anke, Esteve Anna, Merkel Angelika, Raineri Emanuele, Agueda Lidia, Blanc Julie, Richardson David, Clarke Laura, Datta Avik, Russiñol Nuria, Queirós Ana C., Beekman Renée, Rodríguez-Madoz Juan R., San José-Enériz Edurne, Fang Fang, Gutiérrez Norma C., García-Verdugo José M., Robson Michael I., Schirmer Eric C., Guruceaga Elisabeth, Martens Joost H. A., Gut Marta, Calasanz Maria J., Flicek Paul, Siebert Reiner, Campo Elías, San Miguel Jesús F., Melnick Ari, Stunnenberg Hendrik G., Gut Ivo G., Prosper Felipe, and Martín-Subero José I.
JournalGenome Res
Date Published2015 Apr
KeywordsCell Differentiation, Cell Line, Tumor, CpG Islands, DNA Methylation, DNA, Neoplasm, Down-Regulation, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Multiple Myeloma, Neoplastic Stem Cells, Plasma Cells, Promoter Regions, Genetic, Transcription Factors

<p>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.</p>

Alternate JournalGenome Res
PubMed ID25644835
PubMed Central IDPMC4381520
Grant List095209 / / Wellcome Trust / United Kingdom