Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons
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Orly L Wapinski Thomas Vierbuchen Kun Qu Qian Yi Lee Soham Chanda Daniel R Fuentes Paul G Giresi Yi Han Ng Samuele Marro Norma F Neff Daniela Drechsel Ben Martynoga Diogo S Castro Ashley E Webb Thomas C Südhof Anne Brunet Francois Guillemot Howard Y Chang Marius WernigAbstract
Direct lineage reprogramming is a promising approach for human disease modeling and regenerative medicine, with poorly understood mechanisms. Here, we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1, Brn2, and Myt1l. Ascl1 acts as an "on-target" pioneer factor by immediately occupying most cognate genomic sites in fibroblasts. In contrast, Brn2 and Myt1l do not access fibroblast chromatin productively on their own; instead, Ascl1 recruits Brn2 to Ascl1 sites genome wide. A unique trivalent chromatin signature in the host cells predicts the permissiveness for Ascl1 pioneering activity among different cell types. Finally, we identified Zfp238 as a key Ascl1 target gene that can partially substitute for Ascl1 during iN cell reprogramming. Thus, a precise match between pioneer factors and the chromatin context at key target genes is determinative for transdifferentiation to neurons and likely other cell types.
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Publisher website (DOI) 10.1016/j.cell.2013.09.028
Europe PubMed Central 24243019
Pubmed 24243019
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