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

被引：108

作者：

Cakouros, Dimitrios ^{[1
]}

Isenmann, Sandra ^{[1
]}

Cooper, Lachlan ^{[1
]}

Zannettino, Andrew ^{[2
,3
]}

Anderson, Peter ^{[4
]}

Glackin, Carlotta ^{[5
]}

Gronthos, Stan ^{[1
,2
]}

机构：

[1] Univ Adelaide, SA Pathol, Dept Haematol, Mesenchymal Stem Cell Grp, Adelaide, SA, Australia

[2] Univ Adelaide, Ctr Stem Cell Res, Robinson Inst, Dept Med, Adelaide, SA, Australia

[3] Univ Adelaide, SA Pathol, Dept Haematol, Myeloma Res Lab,Ctr Canc Biol, Adelaide, SA, Australia

[4] Womens & Childrens Hosp, Australian Craniofacial Unit, Adelaide, SA, Australia

[5] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2012年 / 32卷 / 08期

基金：

英国医学研究理事会;

关键词：

BONE-MARROW; REPLICATIVE SENESCENCE; P16(INK4A) EXPRESSION; INK4A-ARF LOCUS; PROTEINS; FIBROBLASTS; TRANSPLANTATION; CULTIVATION; STRESS;

D O I：

10.1128/MCB.06315-11

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1433 / 1441

页数：9

共 29 条

[1]

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence [J].