Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient

Holger Heyn, Enrique Vida, Sergi Sayols, Jose V. Sanchez-Mut, Sebastian Moran, Ignacio Medina, Juan Sandoval, Laia Simó-Riudalbas, Karolina Szczesna, Dori Huertas, Sole Gatto, Maria R. Matarazzo, Joaquin Dopazo, Manel Esteller

Research output: Contribution to journalArticlepeer-review


The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and rRNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.

Original languageEnglish
Pages (from-to)542-550
Number of pages9
Issue number6
Publication statusPublished - Jun 2012


  • CpG island
  • DNA methylation
  • DNA methyltransferase
  • DNMT3B
  • Histone
  • Immunodeficiency
  • Transposon
  • Whole genome bisulfite sequencing
  • X chromosome

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research


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