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|Title:||Twist-1 Induces Ezh2 Recruitment Regulating Histone Methylation along the Ink4A/Arf Locus in Mesenchymal Stem Cells|
|Citation:||Molecular and Cellular Biology, 2012; 32(8):1433-1441|
|Publisher:||Amer Soc Microbiology|
|Dimitrios Cakouros, Sandra Isenmann, Lachlan Cooper, Andrew Zannettino, Peter Anderson, Carlotta Glackin, and Stan Gronthos|
|Abstract:||The main impairment to tissue maintenance during aging is the reduced capacity for stem cell self-renewal over time due to senescence, the irreversible block in proliferation. We have previously described that the basic helix-loop-helix (bHLH) transcription factor Twist-1 can greatly enhance the life span of bone marrow-derived mesenchymal stem/stromal cells (MSCs). In the present study, we show that Twist-1 potently suppresses senescence and the Ink4A/Arf locus with a dramatic decrease in the expression of p16 and to some extent a decrease in p14. Furthermore, the polycomb group protein and histone methyltransferase Ezh2, which suppresses the Ink4A/Arf locus, was found to be induced by Twist-1, resulting in an increase in H3K27me3 along the Ink4A/Arf locus, repressing transcription of both p16/p14 and senescence of human MSCs. Furthermore, Twist-1 inhibits the expression of the bHLH transcription factor E47, which is normally expressed in senescent MSCs and induces transcription of the p16 promoter. Reduced Twist-1 wild-type expression and function in bone cells derived from Saethre-Chotzen patients also revealed an increase in senescence. These studies for the first time link Twist-1 to histone methylation of the Ink4A/Arf locus by controlling the expression of histone methyltransferases as well as the expression of other bHLH factors.|
|Keywords:||Cells, Cultured; Mesenchymal Stem Cells; Humans; Histone-Lysine N-Methyltransferase; DNA-Binding Proteins; Nuclear Proteins; Histones; Transcription Factors; Gene Expression Regulation; Epigenesis, Genetic; Methylation; Adult; Cyclin-Dependent Kinase Inhibitor p16; Polycomb Repressive Complex 2; Twist-Related Protein 1; Enhancer of Zeste Homolog 2 Protein; Cellular Senescence; Histone Methyltransferases|
|Rights:||Copyright © 2012, American Society for Microbiology. All Rights Reserved.|
|Appears in Collections:||Microbiology and Immunology publications|
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