Research Paper Volume 2, Issue 7 pp 415—431
miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues
- 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
- 4 Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan
- 5 Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158, USA
Received: June 26, 2010 Accepted: July 15, 2010 Published: July 17, 2010
https://doi.org/10.18632/aging.100176How to Cite
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.