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  - Fiedler, David
A1  - Hirsch, Daniela
A1  - El Hajj, Nady
A1  - Yang, Howard H.
A1  - Hu, Yue
A1  - Sticht, Carsten
A1  - Nanda, Indrajit
A1  - Belle, Sebastian
A1  - Rueschoff, Josef
A1  - Lee, Maxwell P.
A1  - Ried, Thomas
A1  - Haaf, Thomas
A1  - Gaiser, Timo
T1  - Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes
JF  - Genes, Chromosomes and Cancer
N2  - Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin‐fixed paraffin‐embedded colorectal low‐grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine‐phosphate‐guanine (CpG) islands were frequently hypermethylated, whereas open sea‐ and shelf‐regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.
KW  - adenoma
KW  - DNA methylation
KW  - epigenetics
KW  - histological subtype
KW  - recurrence
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212676
VL  - 58
IS  - 11
SP  - 783
EP  - 797
ER  -