DLK1-DIO3 imprinted cluster in induced pluripotency: landscape in the mist

Abstract

DLK1-DIO3 represents an imprinted cluster which genes are involved in physiological cell biology as early as the stem cell level and in the pathogenesis of several diseases. Transcription factor-mediated induced pluripotent cells (iPSCs) are considered an unlimited source of patient-specific hematopoietic stem cells for clinical application in patient-tailored regenerative medicine. However, to date there is no marker established able to distinguish embryonic stem cell-equivalent iPSCs or safe human iPSCs. Recent findings suggest that the DLK1-DIO3 locus possesses the potential to represent such a marker but there are also contradictory data. This review aims to report the current data on the topic describing both sides of the coin.

Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity

“…NLRP2 shows retention of allelic imbalance in some individuals but a larger range of variation in reference ratios across individuals. The DIO3-DLK1 imprinted locus harbors the protein coding genes DLK1 , RTL1 and DIO3 and the long non-coding RNAs (lncRNAs) MEG3 and MEG8 , in addition to the largest known microRNA (miRNA) cluster in the human genome (Benetatos et al, 2014). We have shown that DLK1 is affected by variation in allelic imbalance, which suggests that the whole locus is deregulated in iPSCs as previously shown (Nazor et al, 2012; Stadtfeld et al, 2010).…”

Aberrant DNA Methylation in Human iPSCs Associates with MYC-Binding Motifs in a Clone-Specific Manner Independent of Genetics

“…TMEM132D, DPP6, and FAM19A5 ) (Lister et al, 2011; Ruiz et al, 2012). The long non-coding RNA gene MEG3 from the DLK1-D103 imprinting locus, which has been shown to affect pluripotent stem cell function (Benetatos et al, 2014; Carey et al, 2011; Mo et al, 2015; Stadtfeld et al, 2010) was also differentially expressed. These results show that the patterns of the CpG and RNA predictor classes are similar, and that non-genetic factors (e.g.…”

Induction of apoptosis in ovarian cancer cells by miR-493-3p directly targeting AKT2, STK38L, HMGA2, ETS1 and E2F5

“…[22] and gastric CA [23]. It is encoded on the human chromosome 14 (14q32) in the Delta Like Non-Canonical Notch Ligand 1 (DLK1) -Deiodinase, Iodothyronine Type III (DIO3) genomic region in an pattern of imprinted genes, long noncoding RNAs like maternally expressed 3 (Meg3) and Meg8 and several miRNAs [24] [25] (Fig 1 b).…”