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Molecular Mechanisms of Reprogramming Unveiled

The ability to reprogram cells from a differentiated to an embryonic stem cell-like fate, producing induced pluripotent stem cells, or iPSCs, has revolutionized biology.  Although the process appears relatively simple, just add a few transcription factors to some skin cells and treat them right, the molecular mechanisms underpinning this transformation are mostly obscure.  A new paper published in Nature by Asa Abeliovich, M.D., Ph.D., at Columbia University Medical Center and colleagues, sheds light on some of the earliest steps in the reprogramming process.  Dr. Abeliovich’s group used a screening technique to identify factors that could promote reprogramming through epigenetic modifications, chemical modifications to DNA or associated proteins.  The screen turned up one particular protein that improved the efficiency of iPSC production called Parp1, poly(ADP-ribose) polymerase-1.  Further analysis also implicated a second protein, Tet2, ten-eleven translocation-2, in the earliest stages of reprogramming.  Together, Parp1 and Tet2 result in modifications to both DNA and histones that allow the reprogramming factors, typified by Oct4, access to the promoters of target genes.  These results provide insight into the mechanism of reprogramming and cell fate switching, and have implications for human cancers too, as Tet2 function is lost in some cancers.  This research was supported by NYSTEM through two Targeted research awards to Dr. Abeliovich (C024402 and C024403) and an Institutional Development award at Stony Brook University (C022053)

Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, Guarnieri P, Bhagat G, Vanti WB, Shih A, Levine RL, Nik S, Chen EI, Abeliovich A.  Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2.  Nature. 2012 Aug 30;488(7413):652-5.