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https://hdl.handle.net/2440/73274
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Type: | Journal article |
Title: | Twist-1 Induces Ezh2 Recruitment Regulating Histone Methylation along the Ink4A/Arf Locus in Mesenchymal Stem Cells |
Author: | Cakouros, D. Isenmann, S. Cooper, L. Zannettino, A. Anderson, P. Glackin, C. Gronthos, S. |
Citation: | Molecular and Cellular Biology, 2012; 32(8):1433-1441 |
Publisher: | Amer Soc Microbiology |
Issue Date: | 2012 |
ISSN: | 0270-7306 1098-5549 |
Statement of Responsibility: | 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. |
DOI: | 10.1128/MCB.06315-11 |
Published version: | http://dx.doi.org/10.1128/mcb.06315-11 |
Appears in Collections: | Aurora harvest Microbiology and Immunology publications |
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