Article
- The EMBO Journal (2009) 28, 3157 - 3170
- doi:10.1038/emboj.2009.254
Published online: 10 September 2009
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Myc-regulated microRNAs attenuate embryonic stem cell differentiationEMBO Open
Chin-Hsing Lin1, Aimee L Jackson2,3, Jie Guo2, Peter S Linsley2,3 and Robert N Eisenman1
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biology, Rosetta Inpharmatics LLC, Seattle, WA, USA
Correspondence to:
Robert N Eisenman, Division of Basic Sciences, Fred Hutchinson Cancer Research Center A2M-025, 1100 Fairview Avenue N., POB 19024, Seattle, WA 98109-4417, USA. Tel.: +1 206 667 4445; Fax: +1 206 667 6522; E-mail: eisenman@fhcrc.org
3Present address: Regulus Therapeutics, 1896 Rutherford Rd, Carlsbad, CA 92008, USA
Received 27 April 2009; Accepted 23 July 2009
Abstract
Myc proteins are known to have an important function in stem cell maintenance. As Myc has been shown earlier to regulate microRNAs (miRNAs) involved in proliferation, we sought to determine whether c-Myc also affects embryonic stem (ES) cell maintenance and differentiation through miRNAs. Using a quantitative primer-extension PCR assay we identified miRNAs, including, miR-141, miR-200, and miR-429 whose expression is regulated by c-Myc in ES cells, but not in the differentiated and tumourigenic derivatives of ES cells. Chromatin immunoprecipitation analyses indicate that in ES cells c-Myc binds proximal to genomic regions encoding the induced miRNAs. We used expression profiling and seed homology to identify genes specifically downregulated both by these miRNAs and by c-Myc. We further show that the introduction of c-Myc-induced miRNAs into murine ES cells significantly attenuates the downregulation of pluripotency markers on induction of differentiation after withdrawal of the ES cell maintenance factor LIF. In contrast, knockdown of the endogenous miRNAs accelerate differentiation. Our data show that in ES cells c-Myc acts, in part, through a subset of miRNAs to attenuate differentiation.
Keywords:
- differentiation,
- embryonic stem cell,
- microRNA,
- myc
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