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Twist-1 Induces Ezh2 Recruitment Regulating Histone Methylation along the Ink4A/Arf Locus in Mesenchymal Stem Cells

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dc.contributor.authorCakouros, D.
dc.contributor.authorIsenmann, S.
dc.contributor.authorCooper, L.
dc.contributor.authorZannettino, A.
dc.contributor.authorAnderson, P.
dc.contributor.authorGlackin, C.
dc.contributor.authorGronthos, S.
dc.date.issued2012
dc.description.abstractThe 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.
dc.description.statementofresponsibilityDimitrios Cakouros, Sandra Isenmann, Lachlan Cooper, Andrew Zannettino, Peter Anderson, Carlotta Glackin, and Stan Gronthos
dc.identifier.citationMolecular and Cellular Biology, 2012; 32(8):1433-1441
dc.identifier.doi10.1128/MCB.06315-11
dc.identifier.issn0270-7306
dc.identifier.issn1098-5549
dc.identifier.orcidCakouros, D. [0000-0001-6136-0761]
dc.identifier.orcidZannettino, A. [0000-0002-6646-6167]
dc.identifier.orcidAnderson, P. [0000-0002-3730-4652]
dc.identifier.orcidGronthos, S. [0000-0002-6225-3084]
dc.identifier.urihttp://hdl.handle.net/2440/73274
dc.language.isoen
dc.publisherAmer Soc Microbiology
dc.rightsCopyright © 2012, American Society for Microbiology. All Rights Reserved.
dc.source.urihttps://doi.org/10.1128/mcb.06315-11
dc.subjectCells, Cultured
dc.subjectMesenchymal Stem Cells
dc.subjectHumans
dc.subjectHistone-Lysine N-Methyltransferase
dc.subjectDNA-Binding Proteins
dc.subjectNuclear Proteins
dc.subjectHistones
dc.subjectTranscription Factors
dc.subjectGene Expression Regulation
dc.subjectEpigenesis, Genetic
dc.subjectMethylation
dc.subjectAdult
dc.subjectCyclin-Dependent Kinase Inhibitor p16
dc.subjectPolycomb Repressive Complex 2
dc.subjectTwist-Related Protein 1
dc.subjectEnhancer of Zeste Homolog 2 Protein
dc.subjectCellular Senescence
dc.subjectHistone Methyltransferases
dc.titleTwist-1 Induces Ezh2 Recruitment Regulating Histone Methylation along the Ink4A/Arf Locus in Mesenchymal Stem Cells
dc.typeJournal article
pubs.publication-statusPublished

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