TET2 Favors Mesoderm and Hematopoietic Differentiation in Human Embryonic Stem Cells

Abstract 2418

TET2 belongs to the TET family proteins that catalyze 5-methylcytosine (5mc) to 5-hydroxymethylcytosine (hmc) and plays an important role in normal and malignant adult hematopoiesis. The role of TET2 in human hematopoietic development remains unknown. Here we show that TET2 is expressed at low level in human embryonic stem (hES) cell lines and that its expression increases during hematopoietic differentiation in three different hES. TET2 knockdown does not modify hmc level and pluripotent properties of ES cells. However TET2 depletion by two different shRNA skewed differentiation into neuroectoderm at the expense of endoderm and mesoderm. This was associated with a decrease or an increase in promoter methylation of neuroectoderm and meso/endoderm genes, respectively during hES specification. Subsequently, we observed a decrease in hematopoietic progenitors (CD34⁺CD43⁺) and their cloning capacities due to a marked increase in apoptosis. Alteration of hematopoietic differentiation was coupled with a profound alteration in gene expression with up and down regulated genes including the abnormal expression of neuronal genes in hematopoietic cells. Thus our results suggest that TET2 regulates embryonic development by inhibiting neuroectoderm specification and enabling hematopoietic differentiation in hES cells.