Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb.
The dominant effect of transcription factors in imparting expanded potency is best exemplified by the reprogramming of fibroblasts to pluripotent cells using retrovirus-mediated transduction of defined transcription factors. In the murine system, Oct4, Sox2, c-Myc and Klf4 are sufficient to convert fibroblasts to induced pluripotent stem (iPS) cells that have many characteristics of embryonic stem (ES) cells. Here we show that the orphan nuclear receptor Esrrb functions in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts (MEFs) to iPS cells. Esrrb-reprogrammed cells share similar expression and epigenetic signatures as ES cells. These cells are also pluripotent and can differentiate in vitro and in vivo into the three major embryonic cell lineages. Furthermore, these cells contribute to mouse chimaeras and are germline transmissible. In ES cells, Esrrb targets many genes involved in self-renewal and pluripotency. This suggests that Esrrb may mediate reprogramming through the upregulation of ES-cell-specific genes. Our findings also indicate that it is possible to reprogram MEFs without exogenous Klf transcription factors and link a nuclear receptor to somatic cell reprogramming.
Feng
Bo
B
Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore 138672.
Jiang
Jianming
J
Kraus
Petra
P
Ng
Jia-Hui
JH
Heng
Jian-Chien Dominic
JC
Chan
Yun-Shen
YS
Yaw
Lai-Ping
LP
Zhang
Weiwei
W
Loh
Yuin-Han
YH
Han
Jianyong
J
Vega
Vinsensius B
VB
Cacheux-Rataboul
Valere
V
Lim
Bing
B
Lufkin
Thomas
T
Ng
Huck-Hui
HH
D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D004967:Estrogens / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C098925:Esrrb protein, mouse; D004967:Estrogens; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse