期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 51, 页码 E8257-E8266出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1611142114
关键词
artificial transcription factor; genome-scale library; cell fate; reprogramming; gene regulatory networks
资金
- NIH [HL099773]
- W. M. Keck Medical Research Award
- Progenitor Cell Biology Consortium Jump-Start Award [5U01HL099997-05, 101330A]
- Morgridge Biotechnology Wisconsin Distinguished Fellowship Award
- Stem Cell and Regenerative Medicine Training Award
- Genomic Sciences Training Program [5T32HG002760]
- National Science Foundation-Nanoscale Science and Engineering Center grant
Artificial transcription factors (ATFs) are precision-tailored molecules designed to bind DNA and regulate transcription in a preprogrammed manner. Libraries of ATFs enable the high-throughput screening of gene networks that trigger cell fate decisions or phenotypic changes. We developed a genome-scale library of ATFs that display an engineered interaction domain (ID) to enable cooperative assembly and synergistic gene expression at targeted sites. We used this ATF library to screen for key regulators of the pluripotency network and discovered three combinations of ATFs capable of inducing pluripotency without exogenous expression of Oct4 (POU domain, class 5, TF 1). Cognate site identification, global transcriptional profiling, and identification of ATF binding sites reveal that the ATFs do not directly target Oct4; instead, they target distinct nodes that converge to stimulate the endogenous pluripotency network. This forward genetic approach enables cell type conversions without a priori knowledge of potential key regulators and reveals unanticipated gene network dynamics that drive cell fate choices.
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