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Pluripotent stem cells are increasingly used to build therapeutic models, including the transplantation of neural progenitors derived from human embryonic stem cells (hESCs). Recently, long non-coding RNAs (lncRNAs), including delta-like homolog 1 gene and the type III iodothyronine deiodinase gene ( DLK1-DIO3 ) imprinted locus-derived maternally expressed gene 3 ( MEG3 ), were found to be expressed during neural development. The deregulation of these lncRNAs is associated with various neurological diseases. The imprinted locus  DLK1-DIO3  encodes abundant non-coding RNAs (ncRNAs) that are regulated by differential methylation of the locus. We aim to study the correlation between the  DLK1-DIO3 -derived ncRNAs and the capacity of hESCs to differentiate into neural lineages.    Methods  We classified hESC sublines into  MEG3 -ON and  MEG3 -OFF based on the expression levels of  MEG3  and its downstream microRNAs as detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A cDNA microarray was used to analyze the gene expression profiles of hESCs. To investigate the capacity of neural differentiation in  MEG3 -ON and  MEG3 -OFF hESCs, we performed neural lineage differentiation followed by neural lineage marker expression and neurite formation analyses via qRT-PCR and immunocytochemistry, respectively.  MEG3 -knockdown via small interfering RNA (siRNA) and small hairpin RNA (shRNA) was used to investigate the potential causative effect of  MEG3  in regulating neural lineage-related gene expression.    Results   DLK1-DIO3 -derived ncRNAs were repressed in  MEG3 -OFF hESCs compared with those in the  MEG3 -ON hESCs. The transcriptome profile indicated that many genes related to nervous system development and neural-type tumors were differentially expressed in  MEG3 -OFF hESCs. Three independent  MEG3 -knockdown assays using different siRNA and shRNA constructs consistently resulted in downregulation of some neural lineage genes. Lower expression levels of stage-specific neural lineage markers and reduced neurite formation were observed in neural lineage-like cells derived from  MEG3 -OFF-associated hESCs compared with those in the  MEG3 -ON groups at the same time points after differentiation.    Conclusions  Repression of ncRNAs derived from the  DLK1-DIO3  imprinted locus is associated with reduced neural lineage differentiation potential in hESCs.    Electronic supplementary material  The online version of this article (doi:10.1186/scrt535) contains supplementary material, which is available to authorized users.

stem cell research and therapy

Loss of non-coding RNA expression from the DLK1-DIO3 imprinted locus correlates with reduced neural differentiation potential in human embryonic stem cell lines