Weber FA, Bartolomei G, Hottiger MO, Cinelli P
The recently established reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by Takahashi and Yamanaka, represents a valuable tool for future therapeutic applications. To date, the mechanisms underlying this process are still largely unknown. In particular the mechanisms how the Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc) directly drive reprogramming and which additional components are involved are still not yet understood. In this study, we aimed at analyzing the role of ADP-ribosyltransferase diphtheria toxin-like 1 (Artd1; formerly called poly-ADP-ribose polymerase 1 (Parp1)) during reprogramming. We found that poly-ADP-ribosylation (PARylation) of the reprogramming factor Sox2 by Artd1 plays an important role during the first days upon transduction with the reprogramming factors. A process which happens before Artd1 in conjunction with ten-eleven translocation-2 (Tet2) mediates the histone modifications necessary for the establishment of an activated chromatin state at pluripotency loci (e.g., Nanog and Essrb) (1) . Wild type (WT) fibroblasts treated with an Artd1 inhibitor as well as fibroblasts deficient for Artd1 (Artd1 -/-) show strongly decreased reprogramming capacity. Our data indicate that Artd1 mediated PARylation of Sox2 favors its binding to the Fgf4 enhancer, thereby activating Fgf4 expression. The importance of Fgf4 during the first 4 days upon initiation of reprogramming was also highlighted by the observation that exogenous addition of Fgf4 was sufficient to restore the reprogramming capacity of Artd1-/- fibroblast to WT levels. In conclusion, our data clearly show that the interaction between Artd1 and Sox2 is crucial for the first steps of the reprogramming process and that early expression of Fgf4 (d2-d4) is an essential component for the successful generation of iPSCs. Stem Cells 2013.