Abstract
Class IIa histone deacetylases (HDACs) and myocyte enhancer factor 2 (MEF2) proteins compose a signaling module that orchestrates lineage specification during embryogenesis. We show here that this module also regulates the generation of mouse induced pluripotent stem cells by defined transcription factors. Class IIa HDACs and MEF2 proteins rise steadily during fibroblast reprogramming to induced pluripotent stem cells. MEF2 proteins tend to block the process by inducing the expression of Tgfβ cytokines, which impairs the necessary phase of mesenchymal-to-epithelial transition (MET). Conversely, class IIa HDACs endeavor to suppress the activity of MEF2 proteins, thus enhancing the MET and colony formation efficiency. Our work highlights an unexpected role for a developmental axis in somatic cell reprogramming and provides new insight into how the MET is regulated in this context.
Highlights
Somatic cell reprogramming is an inefficient process because of the existence of roadblocks
Class IIa histone deacetylases (HDACs) Regulate Somatic Cell Reprogramming— Given the fundamental role of class IIa HDACs in development [12,13,14], we speculated that they might regulate reprogramming as well. Supporting this idea, we observed by Western blotting that mouse ESCs/iPSCs display higher levels of HDAC4, -5, and -7 than fibroblasts (Fig. 1A)
If this were true, it would imply that developmental programs must become switched on during reprogramming. This in turn would tend to derail the epigenetic transformation and perhaps help explain the low efficiency of the process. In support of such an idea, we have shown that myocyte enhancer factor 2 (MEF2) proteins, a family of transcription factors with a key role in organogenesis [15, 21], augment during reprogramming and impair iPSC generation (Fig. 9)
Summary
Somatic cell reprogramming is an inefficient process because of the existence of roadblocks. Results: Class IIa histone deacetylases and MEF2 proteins increase during mouse fibroblast reprogramming and differentially regulate the expression of Tgf cytokines. Conclusion: This interplay regulates the mesenchymal-to-epithelial transition phase of reprogramming. Class IIa histone deacetylases (HDACs) and myocyte enhancer factor 2 (MEF2) proteins compose a signaling module that orchestrates lineage specification during embryogenesis. We show here that this module regulates the generation of mouse induced pluripotent stem cells by defined transcription factors. Class IIa HDACs and MEF2 proteins rise steadily during fibroblast reprogramming to induced pluripotent stem cells. MEF2 proteins tend to block the process by inducing the expression of Tgf cytokines, which impairs the necessary phase of mesenchymal-to-epithelial transition (MET). Our work highlights an unexpected role for a developmental axis in somatic cell reprogramming and provides new insight into how the MET is regulated in this context
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