Variable allelic expression of imprinted genes in human pluripotent stem cells during differentiation into specialized cell types in vitro

Genomic imprinting is an epigenetic phenomenon by which a subset of genes is asymmetrically expressed in a parent-of-origin manner. However, little is known regarding the epigenetic behaviors of imprinted genes during human development. Here, we show dynamic epigenetic changes in imprinted genes in hESCs during in vitro differentiation into specialized cell types. Out of 9 imprinted genes with single nucleotide polymorphisms, mono-allelic expression for three imprinted genes (H19, KCNQ1OT1, and IPW), and bi- or partial-allelic expression for three imprinted genes (OSBPL5, PPP1R9A, and RTL1) were stably retained in H9-hESCs throughout differentiation, representing imprinting stability. Three imprinted genes (KCNK9, ATP10A, and SLC22A3) showed a loss and a gain of imprinting in a lineage-specific manner during differentiation. Changes in allelic expression of imprinted genes were observed in another hESC line during in vitro differentiation. These findings indicate that the allelic expression of imprinted genes may be vulnerable in a lineage-specific manner in human pluripotent stem cells during differentiation.     

TET family proteins and their role in stem cell differentiation and transformation

One of the main regulators of gene expression during embryogenesis and stem cell differentiation is DNA methylation. The recent identification of hydroxymethylcytosine (5hmC) as a novel epigenetic mark sparked an intense effort to characterize its specialized enzymatic machinery and to understand the biological significance of 5hmC. The recent discovery of recurrent deletions and somatic mutations in the TET gene family, which includes proteins that can hydroxylate methylcytosine (5mC), in a large fraction of myeloid malignancies further suggested a key role for dynamic DNA methylation changes in the regulation of stem cell differentiation and transformation.