细胞期刊(Cell)2013-10-28 9:00 PM

Hierarchical Mechanisms for Direct Reprogramming of Fibroblasts to Neurons

Highlights
- Ascl1 has pioneer activity, accessing closed chromatin to allow other factors to bind - Unlike other pioneer factors, Ascl1 binds its physiologic neural targets in fibroblasts - A trivalent chromatin domain predicts iN reprogramming ability in other cell types - Zfp238 is a direct Ascl1 target and critical mediator of iN cell reprogramming
Summary 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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细胞期刊(Cell)

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