TY  - JOUR
AU  - Monk, David
AU  - Simón, Carlos
AU  - Iglesias-Platas, Isabel
AU  - Moore, Gudrun
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
Symmetric DNA methylation profiles of autosomal genes is associated with equal expression from 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 a unique mechanism for modulating allelic dosage.

-	Methods
We combined direct interrogation of genome-wide methyl-seq datasets with locus-specific methylation and 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 bisulphite PCR in tissues and single-cell derived clonal analysis.

-	Results
We identify an interval of oocyte-derived methylation that manifests as a maternally-methylated differentially methylated region (DMR) in human blastocysts and placenta which switches to a random ASM profile by week 16 of a gestation. Characterization using 5’RACE revealed that the ERICH1-AS1 transcript is linked to DLGAP2 presenting an alternative transcript start site. Quantitative RT-PCR of DLGAP2 suggests 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 reverting to random ASM. This profile has unique parallels with X-chromosome inactivation (XCI) in female mice in which XCI is initially imprinted during pre-implantation development and maintained in the placenta, whilst derivatives of the inner cell mass are subject to random XCI.   Since DLGAP2 has been associated with many neurological disorders, a potential role of allele-specific expression and random ASM may influence the presentation of the phenotypes.
SN  - 2577-5790
UR  - https://doi.org/10.21926/obm.genet.1803026
DO  - 10.21926/obm.genet.1803026
ID  - Monk2018
ER  -