RESEARCH PAPER

AGING, Vol 2, No 7 , pp 415-431
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miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues

Laura R. Saunders 1,2, Amar Deep Sharma 3, Jaime Tawney 1,2, Masato Nakagawa 4, Keisuke Okita 4, Shinya Yamanaka 4,5, Holger Willenbring 3, Eric Verdin 1,2
1 Gladstone Institute of Virology & Immunology, University of California, San Francisco, CA 94158, USA
2 Department of Medicine, University of California, San Francisco, CA 94158, USA
3 Institute for Regeneration Medicine, Department of Surgery, Division of Transplantation, University of California, San Francisco, CA 94158, USA
4Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
5 Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158, USA
Key words:
SIRT1; mouse embryonic stem cells; miRNAs; differentiation; post-transcriptional regulation; reprogramming
Received:
06/26/10; accepted: 07/15/10; published on line: 07/17/10
Corresponding author:
E-mail:

Abstract

SIRT1 is increasingly recognized as a critical regulator of stress responses, replicative senescence, inflammation, metabolism, and aging. SIRT1 expression is regulated transcriptionally and post-transcriptionally, and its enzymatic activity is controlled by NAD+ levels and interacting proteins. We found that SIRT1 protein levels were much higher in mouse embryonic stem cells (mESCs) than in differentiated tissues. miRNAs post-transcriptionally downregulated SIRT1 during mESC differentiation and maintained low levels of SIRT1 expression in differentiated tissues. Specifically, miR-181a and b, miR-9, miR-204, miR-199b, and miR-135a suppressed SIRT1 protein expression. Inhibition of mir-9, the SIRT1-targeting miRNA induced earliest during mESC differentiation, prevented SIRT1 downregulation. Conversely, SIRT1 protein levels were upregulated post-transcriptionally during the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. The regulation of SIRT1 protein levels by miRNAs might provide new opportunities for therapeutic tissue-specific modulation of SIRT1 expression and for reprogramming of somatic cells into iPS cells.