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

Publication ,  Journal Article
Agirre, X; Castellano, G; Pascual, M; Heath, S; Kulis, M; Segura, V; Bergmann, A; Esteve, A; Merkel, A; Raineri, E; Agueda, L; Blanc, J ...
Published in: Genome Res
April 2015

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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Published In

Genome Res

DOI

EISSN

1549-5469

Publication Date

April 2015

Volume

25

Issue

4

Start / End Page

478 / 487

Location

United States

Related Subject Headings

  • Transcription Factors
  • Promoter Regions, Genetic
  • Plasma Cells
  • Neoplastic Stem Cells
  • Multiple Myeloma
  • Humans
  • Genome, Human
  • Gene Expression Regulation, Neoplastic
  • Epigenesis, Genetic
  • Enhancer Elements, Genetic
 

Citation

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Agirre, X., Castellano, G., Pascual, M., Heath, S., Kulis, M., Segura, V., … Martín-Subero, J. I. (2015). Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers. Genome Res, 25(4), 478–487. https://doi.org/10.1101/gr.180240.114
Agirre, Xabier, Giancarlo Castellano, Marien Pascual, Simon Heath, Marta Kulis, Victor Segura, Anke Bergmann, et al. “Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers.Genome Res 25, no. 4 (April 2015): 478–87. https://doi.org/10.1101/gr.180240.114.
Agirre X, Castellano G, Pascual M, Heath S, Kulis M, Segura V, et al. Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers. Genome Res. 2015 Apr;25(4):478–87.
Agirre, Xabier, et al. “Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers.Genome Res, vol. 25, no. 4, Apr. 2015, pp. 478–87. Pubmed, doi:10.1101/gr.180240.114.
Agirre X, Castellano G, Pascual M, Heath S, Kulis M, Segura V, Bergmann A, Esteve A, Merkel A, Raineri E, Agueda L, Blanc J, Richardson D, Clarke L, Datta A, Russiñol N, Queirós AC, Beekman R, Rodríguez-Madoz JR, San José-Enériz E, Fang F, Gutiérrez NC, García-Verdugo JM, Robson MI, Schirmer EC, Guruceaga E, Martens JHA, Gut M, Calasanz MJ, Flicek P, Siebert R, Campo E, Miguel JFS, Melnick A, Stunnenberg HG, Gut IG, Prosper F, Martín-Subero JI. Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers. Genome Res. 2015 Apr;25(4):478–487.

Published In

Genome Res

DOI

EISSN

1549-5469

Publication Date

April 2015

Volume

25

Issue

4

Start / End Page

478 / 487

Location

United States

Related Subject Headings

  • Transcription Factors
  • Promoter Regions, Genetic
  • Plasma Cells
  • Neoplastic Stem Cells
  • Multiple Myeloma
  • Humans
  • Genome, Human
  • Gene Expression Regulation, Neoplastic
  • Epigenesis, Genetic
  • Enhancer Elements, Genetic