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 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 language | English |
|---|---|
| Pages (from-to) | 542-550 |
| Number of pages | 9 |
| Journal | Epigenetics |
| Volume | 7 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2012 |
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Keywords
- CpG island
- DNA methylation
- DNA methyltransferase
- DNMT3B
- Histone
- Immunodeficiency
- Transposon
- Whole genome bisulfite sequencing
- X chromosome
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
Cite this
Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient. / Heyn, Holger; Vida, Enrique; Sayols, Sergi; Sanchez-Mut, Jose V.; Moran, Sebastian; Medina, Ignacio; Sandoval, Juan; Simó-Riudalbas, Laia; Szczesna, Karolina; Huertas, Dori; Gatto, Sole; Matarazzo, Maria R.; Dopazo, Joaquin; Esteller, Manel.
In: Epigenetics, Vol. 7, No. 6, 06.2012, p. 542-550.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient
AU - Heyn, Holger
AU - Vida, Enrique
AU - Sayols, Sergi
AU - Sanchez-Mut, Jose V.
AU - Moran, Sebastian
AU - Medina, Ignacio
AU - Sandoval, Juan
AU - Simó-Riudalbas, Laia
AU - Szczesna, Karolina
AU - Huertas, Dori
AU - Gatto, Sole
AU - Matarazzo, Maria R.
AU - Dopazo, Joaquin
AU - Esteller, Manel
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - CpG island
KW - DNA methylation
KW - DNA methyltransferase
KW - DNMT3B
KW - Histone
KW - Immunodeficiency
KW - Transposon
KW - Whole genome bisulfite sequencing
KW - X chromosome
UR - http://www.scopus.com/inward/record.url?scp=84861920481&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861920481&partnerID=8YFLogxK
U2 - 10.4161/epi.20523
DO - 10.4161/epi.20523
M3 - Article
C2 - 22595875
AN - SCOPUS:84861920481
VL - 7
SP - 542
EP - 550
JO - Epigenetics
JF - Epigenetics
SN - 1559-2294
IS - 6
ER -