The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells

Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dra...

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Bibliographic Details
Published in:The Journal of biological chemistry Vol. 288; no. 25; p. 18439
Main Authors: Sharma, Amit, Diecke, Sebastian, Zhang, Wendy Y, Lan, Feng, He, Chunjiang, Mordwinkin, Nicholas M, Chua, Katrin F, Wu, Joseph C
Format: Journal Article
Language:English
Published: United States 21.06.2013
Subjects:
Adolescent
Age Factors
Aging - genetics
Aging - physiology
Cells, Cultured
Cellular Reprogramming - genetics
Cellular Reprogramming - physiology
Cluster Analysis
Dermis - cytology
Embryoid Bodies - metabolism
Embryoid Bodies - physiology
Fibroblasts - cytology
Fibroblasts - metabolism
Fibroblasts - physiology
Gene Expression Profiling
Humans
Immunohistochemistry
Induced Pluripotent Stem Cells - metabolism
Induced Pluripotent Stem Cells - physiology
MicroRNAs - genetics
Middle Aged
Models, Genetic
Pluripotent Stem Cells - metabolism
Pluripotent Stem Cells - physiology
Reverse Transcriptase Polymerase Chain Reaction
RNA Processing, Post-Transcriptional
Sirtuins - genetics
Sirtuins - metabolism
Sirtuins - physiology
Gene Expression
MicroRNA
Induced pluripotent Stem Cells
Molecular Biology
Aging
Transcription Factors
Embryonic Stem Cell
ISSN:1083-351X, 1083-351X
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Summary:Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dramatic phenotypes of accelerated aging. In keeping with its role in aging, we demonstrated that human dermal fibroblasts (HDFs) from older human subjects were more resistant to reprogramming by classic Yamanaka factors than those from younger human subjects, but the addition of SIRT6 during reprogramming improved such efficiency in older HDFs substantially. Despite the importance of SIRT6, little is known about the molecular mechanism of its regulation. We show, for the first, time posttranscriptional regulation of SIRT6 by miR-766 and inverse correlation in the expression of this microRNA in HDFs from different age groups. Our results suggest that SIRT6 regulates miR-766 transcription via a feedback regulatory loop, which has implications for the modulation of SIRT6 expression in reprogramming of aging cells.
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ISSN:1083-351X
1083-351X
DOI:10.1074/jbc.M112.405928