Editors' ChoiceStem Cells

The Philosopher’s Stone of Reprogramming

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Science Translational Medicine  13 Nov 2013:
Vol. 5, Issue 211, pp. 211ec189
DOI: 10.1126/scitranslmed.3007980

The 16th-century Swiss alchemist Paracelsus (Philippus Aureolus Theophrastus Bombastus von Hohenheim) was a great believer in the philosopher’s stone or alkahest, which he thought was an undiscovered element that could convert stone into gold. The philosopher’s stone remained a dream for centuries but seems to have reemerged at least within the realm of cell biology. A new study by Wapinski et al. brings us closer to understanding the mechanisms underlying the direct conversion of mouse embryonic fibroblasts (stones) into priceless neurons (gold).

Using a genome-wide chromatin immunoprecipitation sequencing approach, the authors discovered a clear hierarchy among the three neuronal transcription factors Ascl1, Brn2, and Myt1l during conversion of embryonic fibroblasts to a neuronal fate. The transcription factor Ascl1 was able to “unlock” the closed chromatin on genes required for neuronal differentiation. Whereas transcription factors usually bind to different sets of target genes depending on the cellular context, the authors revealed a trivalent chromatin signature that appeared to predict the permissiveness in embryonic fibroblasts for Ascl1-dependent neuron conversion. Binding of Ascl1 led to the subsequent recruitment of Brn2 and Myt1l, which were unable to access their neuronal target genes in the absence of Ascl1. The successful recruitment of Brn2 and Myt1l was, however, critical for efficiency during the subsequent stages of neuron maturation.

Although many questions about the exact mechanism of transcriptional reprogramming have still to be addressed, the study is a major step toward the high-efficiency generation of neurons that could be used as replacement therapy for a variety of neurodegenerative diseases.

O. L. Wapinski et al., Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155, 621–635 (2013). [Abstract]

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