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

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Item Type:Article
Title:Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers
Creators Name:Agirre, X. and Castellano, G. and Pascual, M. and Heath, S. and Kulis, M. and Segura, V. and Bergmann, A. and Esteve, A. and Merkel, A. and Raineri, E. and Agueda, L. and Blanc, J. and Richardson, D. and Clarke, L. and Datta, A. and Russiñol, N. and Queirós, A.C. and Beekman, R. and Rodríguez-Madoz, J.R. and San José-Enériz, E. and Fang, F. and Gutiérrez, N.C. and García-Verdugo, J.M. and Robson, M.I. and Schirmer, E.C. and Guruceaga, E. and Martens, J.H.A. and Gut, M. and Calasanz, M.J. and Flicek, P. and Siebert, R. and Campo, E. and Miguel, J.F.S. and Melnick, A. and Stunnenberg, H.G. and Gut, I.G. and Prosper, F. and Martín-Subero, J.I.
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.
Keywords:Cell Differentiation, Tumor Cell Line, CpG Islands, DNA Methylation, Neoplasm DNA, Down-Regulation, Genetic Enhancer Elements, Genetic Epigenesis, Neoplastic Gene Expression Regulation, Human Genome, Multiple Myeloma, Neoplastic Stem Cells, Plasma Cells, Genetic Promoter Regions, Transcription Factors
Source:Genome Research
Publisher:Cold Spring Harbor Laboratory Press
Page Range:478-487
Date:April 2015
Official Publication:https://doi.org/10.1101/gr.180240.114
PubMed:View item in PubMed

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