miR-34 miRNAs provide a barrier for somatic cell reprogramming.
Somatic reprogramming induced by defined transcription factors is a low-efficiency process that is enhanced by p53 deficiency. So far, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation, indicating that additional p53 targets may regulate this process. Here, we demonstrate that miR-34 microRNAs (miRNAs), particularly miR-34a, exhibit p53-dependent induction during reprogramming. Mir34a deficiency in mice significantly increased reprogramming efficiency and kinetics, with miR-34a and p21 cooperatively regulating somatic reprogramming downstream of p53. Unlike p53 deficiency, which enhances reprogramming at the expense of iPSC pluripotency, genetic ablation of Mir34a promoted iPSC generation without compromising self-renewal or differentiation. Suppression of reprogramming by miR-34a was due, at least in part, to repression of pluripotency genes, including Nanog, Sox2 and Mycn (also known as N-Myc). This post-transcriptional gene repression by miR-34a also regulated iPSC differentiation kinetics. miR-34b and c similarly repressed reprogramming; and all three miR-34 miRNAs acted cooperatively in this process. Taken together, our findings identified miR-34 miRNAs as p53 targets that play an essential role in restraining somatic reprogramming.
Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA.
Yong Jin
YJ
Choi
Chao-Po
CP
Lin
Jaclyn J
JJ
Ho
Xingyue
X
He
Nobuhiro
N
Okada
Pengcheng
P
Bu
Yingchao
Y
Zhong
Sang Yong
SY
Kim
Margaux J
MJ
Bennett
Caifu
C
Chen
Arzu
A
Ozturk
Geoffrey G
GG
Hicks
Greg J
GJ
Hannon
Lin
L
He
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D018920:Coculture Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc; D018398:Homeodomain Proteins / Q000235:genetics; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D055748:SOXB1 Transcription Factors / Q000235:genetics; D013724:Teratoma / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D016159:Tumor Suppressor Protein p53