René Dirks, with other members from the lab of Hendrik Marks, theme Cancer development and immune defense, show in a paper in Epigenetics & Chromatin that genomic imprinting (genes expressed from the paternal or maternal allele only) is often lost in cultured embryonic stem cells.Publication in Epigenetics & Chromatin: link.
Genomic imprinting, resulting in parent-of-origin specific gene expression, plays a critical role in mammalian development. We applied allele-specific RNA-seq to assay imprinted genes in tissues from early embryonic mouse tissues between E3.5 and E7.25 and in pluripotent cell lines to evaluate maintenance of imprinted gene expression. For the cell lines, we include embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) derived from fertilized embryos and from embryos obtained after nuclear transfer (NT) or parthenogenetic activation (PGA).
Global analysis shows that proper imprinted gene expression as observed in embryonic tissues is largely lost in the ESC lines included in this study. Differentiation of ESC lines to embryoid bodies or NPCs does not restore monoallelic expression of imprinted genes, neither did reprogramming of the serum-cultured ESCs to the pluripotent ground state by the use of 2 kinase inhibitors. Fertilized EpiSC and EpiSC-NT lines largely maintain imprinted gene expression, as did EpiSC-PGA lines that show known paternally expressed genes being silent and known maternally expressed genes consistently showing doubled expression. Notably, two EpiSC-NT lines show aberrant silencing of Rian and Meg3, two critically imprinted genes in mouse iPSCs. With respect to female EpiSC, most of the lines displayed completely skewed X inactivation suggesting a (near) clonal origin.
Our analysis provides a comprehensive overview of imprinted gene expression in pluripotency and provides a benchmark to allow identification of cell lines that faithfully maintain imprinted gene expression.and therefore retain full developmental potential.
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