Hierarchical Mechanisms for Direct Reprogramming of Fibroblasts to Neurons

被引：466

作者：

Wapinski, Orly L. ^{[1
,2
,3
]}

Vierbuchen, Thomas ^{[3
,4
,5
]}

Qu, Kun ^{[1
,2
]}

Lee, Qian Yi ^{[4
,5
,6
]}

Chanda, Soham ^{[4
,5
]}

Fuentes, Daniel R. ^{[3
,4
,5
]}

Giresi, Paul G. ^{[1
,2
]}

Ng, Yi Han ^{[4
,5
,7
]}

Marro, Samuele ^{[4
,5
]}

Neff, Norma F. ^{[6
]}

Drechsel, Daniela ^{[10
]}

Martynoga, Ben ^{[10
]}

Castro, Diogo S. ^{[11
]}

Webb, Ashley E. ^{[8
]}

Suedhof, Thomas C. ^{[1
,9
]}

Brunet, Anne ^{[3
,8
]}

Guillemot, Francois ^{[10
]}

Chang, Howard Y. ^{[1
,2
,3
]}

Wernig, Marius ^{[3
,4
,5
]}

机构：

[1] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

[2] Stanford Univ, Program Epithelial Biol, Stanford, CA 94305 USA

[3] Stanford Univ, Program Canc Biol, Stanford, CA 94305 USA

[4] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA

[10] Natl Inst Med Res, MRC, Div Mol Neurobiol, London NW7 1AA, England

[11] Inst Gulbenkian Ciencias, Div Mol Neurobiol, P-2780156 Oeiras, Portugal

来源：

CELL | 2013年 / 155卷 / 03期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

ACHAETE-SCUTE HOMOLOG-1; FUNCTIONAL-NEURONS; TRANSCRIPTIONAL ACTIVATION; DEFINED FACTORS; STEM-CELLS; CONVERSION; CHROMATIN; DEMETHYLASES; FINGER; GENOME;

D O I：

10.1016/j.cell.2013.09.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：621 / 635

页数：15

共 41 条

[1] Direct Reprogramming of Adult Human Fibroblasts to Functional Neurons under Defined Conditions [J].