TY  - JOUR
A1  - Haertle, Larissa
A1  - Maierhofer, Anna
A1  - Böck, Julia
A1  - Lehnen, Harald
A1  - Böttcher, Yvonne
A1  - Blüher, Matthias
A1  - Schorsch, Martin
A1  - Potabattula, Ramya
A1  - El Hajj, Nady
A1  - Appenzeller, Silke
A1  - Haaf, Thomas
T1  - Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals
JF  - PLoS ONE
N2  - Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted MEST promoter and the paternally imprinted MEG3 intergenic (IG) differentially methylated region (DMR) in fetal cord blood, adult blood, and visceral adipose tissue. Epimutations were defined as paternal or maternal alleles with >50% aberrantly (de)methylated CpG sites, showing the wrong methylation imprint. The epimutation rates (range 2–66%) of the paternal MEST and the maternal MEG3 IG DMR allele, which should be completely unmethylated, were significantly higher than those (0–15%) of the maternal MEST and paternal MEG3 alleles, which are expected to be fully methylated. This hypermethylation of the non-imprinted allele (HNA) was independent of parental origin. Very low epimutation rates in sperm suggest that HNA occurred after fertilization. DBS with Illumina (MiSeq) technology confirmed HNA for the MEST promoter and the MEG3 IG DMR, and to a lesser extent, for the paternally imprinted secondary MEG3 promoter and the maternally imprinted PEG3 promoter. HNA leads to biallelic methylation of imprinted genes in a considerable proportion of normal body cells (somatic mosaicism) and is highly variable between individuals. We propose that during development and differentiation maintenance of differential methylation at most imprinting control regions may become to some extent redundant. The accumulation of stochastic and environmentally-induced methylation errors on the non-imprinted allele may increase epigenetic diversity between cells and individuals.
KW  - DNA methylation
KW  - genomic imprinting
KW  - polymerase chain reaction
KW  - blood
KW  - epigenetics
KW  - sequence alignment
KW  - sperm
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170433
VL  - 12
IS  - 8
ER  - 
TY  - JOUR
A1  - Pfeiffer, Susanne
A1  - Krüger, Jacqueline
A1  - Maierhofer, Anna
A1  - Böttcher, Yvonne
A1  - Klöting, Nora
A1  - El Hajj, Nady
A1  - Schleinitz, Dorit
A1  - Schön, Michael R.
A1  - Dietrich, Arne
A1  - Fasshauer, Mathias
A1  - Lohmann, Tobias
A1  - Dreßler, Miriam
A1  - Stumvoll, Michael
A1  - Haaf, Thomas
A1  - Blüher, Matthias
A1  - Kovacs, Peter
T1  - Hypoxia-inducible factor 3A gene expression and methylation in adipose tissue is related to adipose tissue dysfunction
JF  - Scientific Reports
N2  - Recently, a genome-wide analysis identified DNA methylation of the HIF3A (hypoxia-inducible factor 3A) as strongest correlate of BMI. Here we tested the hypothesis that HIF3A mRNA expression and CpG-sites methylation in adipose tissue (AT) and genetic variants in HIF3A are related to parameters of AT distribution and function. In paired samples of subcutaneous AT (SAT) and visceral AT (VAT) from 603 individuals, we measured HIF3A mRNA expression and analyzed its correlation with obesity and related traits. In subgroups of individuals, we investigated the effects on HIF3A genetic variants on its AT expression (N = 603) and methylation of CpG-sites (N = 87). HIF3A expression was significantly higher in SAT compared to VAT and correlated with obesity and parameters of AT dysfunction (including CRP and leucocytes count). HIF3A methylation at cg22891070 was significantly higher in VAT compared to SAT and correlated with BMI, abdominal SAT and VAT area. Rs8102595 showed a nominal significant association with AT HIF3A methylation levels as well as with obesity and fat distribution. HIF3A expression and methylation in AT are fat depot specific, related to obesity and AT dysfunction. Our data support the hypothesis that HIF pathways may play an important role in the development of AT dysfunction in obesity.
KW  - gene expression
KW  - adipose
KW  - hypoxia-inducible factor 3A
KW  - adipose tissue dysfunction
KW  - obesity
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167662
VL  - 6
IS  - 27969
ER  -