title: Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.
abstract: 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 ribosomal RNA 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.
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat; Barcelona, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.forename: Enrique
authors.initials: E
authors.lastname: Vidal
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sanchez-Mut
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.forename: Ignacio
authors.initials: I
authors.lastname: Medina
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.forename: Laia
authors.initials: L
authors.lastname: Simó-Riudalbas
authors.forename: Karolina
authors.initials: K
authors.lastname: Szczesna
authors.forename: Dori
authors.initials: D
authors.lastname: Huertas
authors.forename: Sole
authors.initials: S
authors.lastname: Gatto
authors.forename: Maria R
authors.initials: MR
authors.lastname: Matarazzo
authors.forename: Joaquin
authors.initials: J
authors.lastname: Dopazo
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D001402:B-Lymphocytes; D002461:Cell Line, Transformed; D002675:Child, Preschool; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005145:Face / Q000002:abnormalities; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D000081207:Primary Immunodeficiency Diseases; D017422:Sequence Analysis, DNA; D013447:Sulfites; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D013447:Sulfites; D000097584:DNA Methyltransferase 3B; C042345:hydrogen sulfite