TY  - JOUR
A1  - Schneider, Eberhard
A1  - Pliushch, Galyna
A1  - El Hajj, Nady
A1  - Galetzka, Danuta
A1  - Puhl, Alexander
A1  - Schorsch, Martin
A1  - Frauenknecht, Katrin
A1  - Riepert, Thomas
A1  - Tresch, Achim
A1  - Mueller, Annette M.
A1  - Coerdt, Wiltrud
A1  - Zechner, Ulrich
A1  - Haaf, Thomas
T1  - Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns
N2  - DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of genespecific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.
KW  - Medizin
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68371
ER  - 
TY  - JOUR
A1  - Galetzka, Danuta
A1  - Hansmann, Tamara
A1  - El Hajj, Nady
A1  - Weis, Eva
A1  - Irmscher, Benjamin
A1  - Ludwig, Marco
A1  - Schneider-Rätzke, Brigitte
A1  - Kohlschmidt, Nicolai
A1  - Beyer, Vera
A1  - Bartsch, Oliver
A1  - Zechner, Ulrich
A1  - Spix, Claudia
A1  - Haaf, Thomas
T1  - Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer
JF  - Epigenetics
N2  - We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development.
KW  - BRCA1
KW  - childhood cancer
KW  - DNA Methylation
KW  - epimutation
KW  - monozygotic twins
KW  - secondary cancer
KW  - somatic mosaicism
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125386
VL  - 7
IS  - 1
ER  -