Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs

Abstract

Background Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines. Results We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual’s methylation status is associated with the mother’s age and socioeconomic status, but not with the individual’s own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood. Conclusions These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region.

Methylation pattern of polymorphically imprinted nc886 is not conserved across mammalia

“…The telomeric CTCF binding site was shown to interact with a CTCF binding site (chr5:135222814-135223707) locating near the IL9 gene in the CTCF CiA-PET data. This prediction is in line with our previous finding indicating that genetic polymorphisms near IL9 gene are associated with the expression of nc886 RNAs [10]. Together these results suggest that the evolutionally conserved telomeric CTCF binding site of nc886 interacts with CTCF binding sites near IL9 gene, possibly forming a topologically associating domain (TAD), or an interaction within one (sub-TAD), and bringing the suggested enhancer area near the nc886 gene [42].…”

“…Availability of data and materials: All methylation data utilized is available in GEO, under accession numbers GSE136296, GSE41782, GSE103287, GSE98549, GSE105018, GSE64490 and GSE72778. In humans a bimodal methylation pattern can be detected, similar to blood and in line with expected population distribution of non-and hemi-methylated individuals [10]. In Old World monkeys the between individual variation is bigger than in apes.…”

“…Non-coding RNA 886 is encoded in chromosome 5q31.1, from a 1.9kb long, differentially methylated region (DMR), the boundaries of which are marked by two CTCF binding sites [7,8]. This DMR has been shown to present maternal imprinting in ~75% of individuals in several populations [7,9,10]. This means that while in all individuals the paternal allele is unmethylated, in approximately 75% of individuals the maternal allele is methylated (individuals present a 50% methylation level at nc886 locus and are hemimethylated) and in the remaining 25% of individuals the maternal allele is unmethylated (individuals present a 0% methylation level at the nc886 locus and are non-methylated).…”

Methylation pattern of polymorphically imprinted nc886 is not conserved across mammalia

“…The nc886 differentially methylated region (DMR) is 1.9-kb long, and its boundaries are marked by two CTCF binding sites [ 10 , 15 ]. This DMR has been shown to present maternal imprinting in ~75% of individuals in several populations [ 10 , 12 , 16 ]. This means that while in all individuals the paternal allele is unmethylated, in approximately 75% of individuals the maternal allele is methylated (individuals present a 50% methylation level at nc886 locus) and in the remaining 25% of individuals the maternal allele is unmethylated (individuals present a 0% methylation level at the nc886 locus).…”

“…Expression of nc886 RNAs is strongly associated with the methylation status of the nc886 locus. Individuals with non-methylated nc886 present approximately two-fold levels of nc886 RNAs in blood, as compared to individuals with monoallelic methylation [ 16 ], thus implying allele-specific expression. However, allele-specific expression has not been experimentally shown, as the 102 nt transcript does not harbour SNPs [ 10 ].…”