Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation

被引:185
作者
Dhawan, Sangeeta [1 ]
Tschen, Shuen-Ing [1 ]
Bhushan, Anil [1 ,2 ]
机构
[1] Univ Calif Los Angeles, Dept Med, Larry L Hillblom Islet Res Ctr, Los Angeles, CA 90024 USA
[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA
关键词
MLL1; H2A ubiquitylation; aging; diabetes; regeneration; SELF-RENEWAL; ADULT; EXPRESSION; EXPANSION; PROTEINS;
D O I
10.1101/gad.1742609
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The molecular mechanisms that regulate the age-induced increase of p16(INK4a) expression associated with decreased beta-cell proliferation and regeneration are not well understood. We report that in aged islets, derepression of the Ink4a/Arf locus is associated with decreased Bmi-1 binding, loss of H2A ubiquitylation, increased MLL1 recruitment, and a concomitant increase in H3K4 trimethylation. During beta-cell regeneration these histone modifications are reversed resulting in reduced p16(INK4a) expression and increased proliferation. We suggest that PcG and TrxG proteins impart a combinatorial code of histone modifications on the Ink4a/Arf locus to control beta-cell proliferation during aging and regeneration.
引用
收藏
页码:906 / 911
页数:6
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