ERRs Mediate a Metabolic Switch Required for Somatic Cell Reprogramming

We show that key regulators of oxidative metabolism, the Estrogen Related Receptors (ERRs) and the PGC-1 co-activators, are transiently induced during somatic cell reprogramming. Bioenergetic assays reveal that while glycolysis increases throughout the reprogramming transition, the early stages feature a transient oxidative phosphorylation (OXPHOS) burst. Up-regulation of ERRa or ? is a prerequisite for the OXPHOS burst in human and mouse cells, respectively, and failure to induce this metabolic switch collapses the reprogramming process. We identify a Sca1-/CD34- sub-population of early reprogramming cells with enhanced ERR? and PGC-1ß expression as bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic switch prior to establishment of induced pluripotency.

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