OCT4 and SOX2 Work as Transcriptional Activators in Reprogramming Human Fibroblasts

Publication date: 15 August 2017
Source:Cell Reports, Volume 20, Issue 7
Author(s): Santosh Narayan, Gene Bryant, Shivangi Shah, Georgina Berrozpe, Mark Ptashne
SOX2 and OCT4, in conjunction with KLF4 and cMYC, are sufficient to reprogram human fibroblasts to induced pluripotent stem cells (iPSCs), but it is unclear if they function as transcriptional activators or as repressors. We now show that, like OCT4, SOX2 functions as a transcriptional activator. We substituted SOX2-VP16 (a strong activator) for wild-type (WT) SOX2, and we saw an increase in the efficiency and rate of reprogramming, whereas the SOX2-HP1 fusion (a strong repressor) eliminated reprogramming. We report that, at an early stage of reprogramming, virtually all DNA-bound OCT4, SOX2, and SOX2-VP16 were embedded in putative enhancers, about half of which were created de novo. Those associated with SOX2-VP16 were, on average, stronger than those bearing WT SOX2. Many newly created putative enhancers were transient, and many transcription factor locations on DNA changed as reprogramming progressed. These results are consistent with the idea that, during reprogramming, there is an intermediate state that is distinct from both parental cells and iPSCs.

Graphical abstract

Teaser

Narayan et al. show that substituting SOX2 with the strong activator SOX2-VP16 increases reprogramming efficiency of human fibroblasts, especially those cultured from older donors. Thousands of enhancers are created and destroyed in the course of reprogramming, including many enhancers created at binding sites of OCT4 or SOX2.


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