TY  - JOUR
AU  - Monk, David
AU  - Simón, Carlos
AU  - Iglesias-Platas, Isabel
AU  - Moore, Gudrun E.
AU  - Ishida, Miho
AU  - Poo-Llanillo, Maria Eugenia
AU  - Medrano, Jose
AU  - Guara Ciurana, Sonia
AU  - Monteagudo-Sánchez, Ana
AU  - Sánchez-Delgado, Marta
PY  - 2018
DA  - 2018/07/29
TI  - Epigenetic Symmetry of DLGAP2: Pre-Implantation Maternal Methylation Switches to a Random Monoallelic Profile in Somatic Tissues
JO  - OBM Genetics
SP  - 026
VL  - 02
IS  - 03
AB  - Background: Symmetrical DNA methylation profiles of autosomal genes are associated with equal expression by both alleles. Genes with an allelic imbalance or monoallelic expression are associated with discrete intervals of allele-specific methylation (ASM), as highlighted by genomic imprinting, X-chromosome inactivation and genotype-driven ASM. However, a more complex pattern has been described in which random monoallelic methylation provides cells with a unique mechanism for modulating allelic dosage. Methods: We combined direct interrogation of genome-wide methyl-seq datasets with locus-specific methylation with expression analysis to characterize the epigenetic profile of a CpG island associated with the DLGAP2 gene. The random nature of the ASM was confirmed using both bisulfite PCR in tissues and single cell-derived clonal analysis. Results: We identified an interval of oocyte-derived methylation manifested as a maternally methylated differentially methylated region (DMR) in human blastocysts and placenta. This switched to a random ASM profile by week 16 of gestation. Characterization using 5’ RACE-PCR revealed linkage of the ERICH1-AS1 transcript to DLGAP2, presenting an alternative transcription start site. Quantitative RT-PCR of DLGAP2 suggested a highly restricted expression profile limited to testis and brain, with allelic RT-PCR demonstrating robust biallelic expression. Conclusions: While many intervals subject to transient maternal methylation in the human pre-implantation embryo resolve to a fully unmethylated state in somatic tissues, we describe the first example of a CpG island converting to a random ASM profile. This profile has parallels with X-chromosome inactivation (XCI) in female mice, in which XCI is initially imprinted during pre-implantation development and maintained in the placenta, while derivatives of the inner cell mass are subject to random XCI. DLGAP2 has been associated with many neurological disorders, indicating a potential role of allele-specific expression and random ASM in the presentation of the disease phenotypes.
SN  - 2577-5790
UR  - https://doi.org/10.21926/obm.genet.1803026
DO  - 10.21926/obm.genet.1803026
ID  - Monk2018
ER  -