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Title: Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers
Author: Agirre, Xabier
Castellano, Giancarlo
Pascual, Marien
Heath, Simon
Kulis, Marta
Segura, Victor
Bergmann, Anke
Esteve Codina, Anna
Merkel, Angelika
Raineri, Emanuele
Agueda Calpena, Lídia
Blanc, Julie
Richardson, David
Clarke, Laura
Datta, Avik
Russiñol, Nuria
Queiros, 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, María José
Flicek, Paul
Siebert, Reiner
Campo Güerri, Elias
San Miguel, Jesús F.
Melnick, Ari
Stunnenberg, Hendrik G.
Gut, Ivo
Prosper, Felipe
Martín-Subero, José Ignacio
Keywords: Mielomatosi
Cèl·lules B
Myeloproliferative disorders
B cells
Issue Date: 2-Feb-2015
Publisher: Cold Spring Harbor Laboratory Press
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.
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It is part of: Genome Research, 2015, vol. 25, num. 4, p. 478-487
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ISSN: 1088-9051
Appears in Collections:Articles publicats en revistes (Fonaments Clínics)

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