The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells.
Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) with the introduction of Oct4, Sox2, Klf4, and c-Myc. Among these four factors, Oct4 is critical in inducing pluripotency because no transcription factor can substitute for Oct4, whereas Sox2, Klf4, and c-Myc can be replaced by other factors. Here we show that the orphan nuclear receptor Nr5a2 (also known as Lrh-1) can replace Oct4 in the derivation of iPSCs from mouse somatic cells, and it can also enhance reprogramming efficiency. Sumoylation mutants of Nr5a2 with enhanced transcriptional activity can further increase reprogramming efficiency. Genome-wide location analysis reveals that Nr5a2 shares many common gene targets with Sox2 and Klf4, which suggests that the transcription factor trio works in concert to mediate reprogramming. We also show that Nr5a2 works in part through activating Nanog. Together, we show that unrelated transcription factors can replace Oct4 and uncovers an exogenous Oct4-free reprogramming code.
Heng
Jian-Chien Dominic
JC
Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672, Singapore.
Feng
Bo
B
Han
Jianyong
J
Jiang
Jianming
J
Kraus
Petra
P
Ng
Jia-Hui
JH
Orlov
Yuriy L
YL
Huss
Mikael
M
Yang
Lin
L
Lufkin
Thomas
T
Lim
Bing
B
Ng
Huck-Hui
HH
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C431936:Nr5a2 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D055748:SOXB1 Transcription Factors; D025842:SUMO-1 Protein; C527783:Sox2 protein, mouse; D054339:Steroidogenic Factor 1; C515058:steroidogenic factor 1, mouse