Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell. 2013 Oct 24;155(3):621-35. doi: 10.1016/j.cell.2013.09.028. Epub 2013 Oct 24.

Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons.

Author information

1
Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA; Program in Cancer Biology, Stanford University, Stanford, CA 94305, USA.

Abstract

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.

Comment in

PMID:
24243019
PMCID:
PMC3871197
DOI:
10.1016/j.cell.2013.09.028
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center