MiR-34 miRNAs provide a barrier for somatic cell reprogramming

Choi, Y. J., Lin, C. P., Ho, J. J., He, X., Okada, N., Bu, P., Zhong, Y., Kim, S. Y., Bennett, M. J., Chen, C., Ozturk, A., Hicks, G. G., Hannon, G. J., He, L. (2011) MiR-34 miRNAs provide a barrier for somatic cell reprogramming. Nature Cell Biology, 13 (11). pp. 1353-1360. ISSN 14657392 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22020437
DOI: 10.1038/ncb2366

Abstract

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. © 2011 Macmillan Publishers Limited. All rights reserved.

Item Type: Paper
Uncontrolled Keywords: microRNA microRNA 34a microrna 34b microRNA 34c protein p21 protein p53 unclassified drug animal cell article controlled study embryonic stem cell gene gene repression mouse NANOG gene nonhuman oncogene c myb pluripotent stem cell priority journal procedures concerning cells protein deficiency protein induction regulatory mechanism somatic cell reprogramming sox2 gene Animals Cell Differentiation Cells, Cultured Coculture Techniques Cyclin-Dependent Kinase Inhibitor p21 Female Gene Expression Regulation, Developmental Genes, myc Homeodomain Proteins Induced Pluripotent Stem Cells Kinetics Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Mice, Nude Mice, Transgenic MicroRNAs Nuclear Reprogramming Octamer Transcription Factor-3 RNA Interference SOXB1 Transcription Factors Teratoma Tumor Suppressor Protein p53 Mus
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Gene Targeting Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Hannon lab
CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service
Depositing User: Matt Covey
Date Deposited: 09 Jan 2013 16:14
Last Modified: 30 Oct 2015 16:14
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26430

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