| First Author | Wapinski OL | Year | 2013 |
| Journal | Cell | Volume | 155 |
| Issue | 3 | Pages | 621-35 |
| PubMed ID | 24243019 | Mgi Jnum | J:241054 |
| Mgi Id | MGI:5897542 | Doi | 10.1016/j.cell.2013.09.028 |
| Citation | Wapinski OL, et al. (2013) Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155(3):621-35 |
| abstractText | 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. |
