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 
one (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 that happens before 
Artd1 in conjunction with 10-11 translocation-2 (Tet2) mediates the histone 
modifications necessary for the establishment of an activated chromatin state at 
pluripotency loci (e.g., Nanog and Essrb) [Nature 2012;488:652-655]. 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 fibroblast growth factor 4 (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 (day 2 to day 4) is an essential component for the 
successful generation of iPSCs.