miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues.
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.
Saunders
Laura R
LR
Gladstone Institute of Virology and Immunology, University of California, San Francisco, 94158, USA.
Sharma
Amar Deep
AD
Tawney
Jaime
J
Nakagawa
Masato
M
Okita
Keisuke
K
Yamanaka
Shinya
S
Willenbring
Holger
H
Verdin
Eric
E
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D016922:Cellular Senescence / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D015195:Drug Design; D053595:Embryonic Stem Cells / Q000502:physiology; D042822:Genomic Instability / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000502:physiology; D009928:Organ Specificity; D014176:Protein Biosynthesis / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000502:physiology
D035683:MicroRNAs; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1