The IG-DMR and the MEG3-DMR at Human Chromosome 14q32.2: Hierarchical Interaction and Distinct Functional Properties as Imprinting Control Centers

Abstract

Human chromosome 14q32.2 harbors the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the postfertilization-derived secondary MEG3-DMR, together with multiple imprinted genes. Although previous studies in cases with microdeletions and epimutations affecting both DMRs and paternal/maternal uniparental disomy 14-like phenotypes argue for a critical regulatory function of the two DMRs for the 14q32.2 imprinted region, the precise role of the individual DMR remains to be clarified. We studied an infant with upd(14)pat body and placental phenotypes and a heterozygous microdeletion involving the IG-DMR alone (patient 1) and a neonate with upd(14)pat body, but no placental phenotype and a heterozygous microdeletion involving the MEG3-DMR alone (patient 2). The results generated from the analysis of these two patients imply that the IG-DMR and the MEG3-DMR function as imprinting control centers in the placenta and the body, respectively, with a hierarchical interaction for the methylation pattern in the body governed by the IG-DMR. To our knowledge, this is the first study demonstrating an essential long-range imprinting regulatory function for the secondary DMR.

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

“…The 14q32 region has been associated with imprinting disorders 35 and tumorigenesis. 36 In particular, this genomic area harbors three differentially methylated regions 37,38 described to coordinately regulate (1) the paternally expressed genes DLK1 and RTL1 (retrosposon-like1) and (2) the maternally expressed genes MEG3 (long intergenic non-protein coding RNA 23 or GTL2), RTL-antisense transcript, MEG8, MEG9, and several polyadenylated C/D box small nucleolar (sno)RNAs 39,40 and microRNAs 20,[40][41][42][43] ( Figure 2, Tables S6 and S7). From our analysis, we validated the known imprinting statuses of MEG3, MEG8, MEG9, DLK1, and RTL-antisense transcripts (Tables S7), but the DIO3 and RTL1 genes were not detectable in fibroblasts.…”

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

“…Until recently, TS14 was regarded as a differential molecular diagnosis of Prader-Willi syndrome (PWS), but the broadening of genetic testing shows that the TS14 phenotype is heterogeneous, overlaps in early childhood with that of SRS, and is not mandatorily associated with (mild) psychomotoric retardation [21]. The impressive result of the application of multilocus tests in ID diagnostics is therefore obvious as a growing number of patients with Temple syndrome (TS14) can be identified among patients referred as SRS [22]. This illustrates the need for a comprehensive diagnostic algorithm in the testing of SRS.…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…In contrast, MNCs exhibit higher methylation at this locus, in agreement with a recent report on imprinting in human tissues [124]. Though the exact mechanism of imprinting at the DLK1-MEG3 locus has yet to be determined, the association of methylation at the IG-DMR and MEG3 DMR is similar to that of the IGF2-H19 locus [99]. I found that the DLK1/MEG3 expression ratio is significantly higher in NTera2 cells than MNCs, in agreement with their respective methylation patterns at both DMRs within this locus ( Figure 27A).…”