TY - JOUR
T1 - Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers
AU - Agirre, Xabier
AU - Castellano, Giancarlo
AU - Pascual, Marien
AU - Heath, Simon
AU - Kulis, Marta
AU - Segura, Victor
AU - Bergmann, Anke
AU - Esteve, Anna
AU - Merkel, Angelika
AU - Raineri, Emanuele
AU - Agueda, Lidia
AU - Blanc, Julie
AU - Richardson, David
AU - Clarke, Laura
AU - Datta, Avik
AU - Russiñol, Nuria
AU - Queirós, Ana C.
AU - Beekman, Renée
AU - Rodríguez-Madoz, Juan R.
AU - José-Enériz, Edurne San
AU - Fang, Fang
AU - Gutiérrez, Norma C.
AU - García-Verdugo, José M.
AU - Robson, Michael I.
AU - Schirmer, Eric C.
AU - Guruceaga, Elisabeth
AU - Martens, Joost H.A.
AU - Gut, Marta
AU - Calasanz, Maria J.
AU - Flicek, Paul
AU - Siebert, Reiner
AU - Campo, Elías
AU - San Miguel, Jesús F.
AU - Melnick, Ari
AU - Stunnenberg, Hendrik G.
AU - Gut, Ivo G.
AU - Prosper, Felipe
AU - Martín-Subero, José I.
N1 - Publisher Copyright:
© 2015 Agirre et al.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84927709359&partnerID=8YFLogxK
U2 - 10.1101/gr.180240.114
DO - 10.1101/gr.180240.114
M3 - Article
C2 - 25644835
AN - SCOPUS:84927709359
SN - 1088-9051
VL - 25
SP - 478
EP - 487
JO - Genome Research
JF - Genome Research
IS - 4
ER -