Regulation of PPARgamma Expression and Adipogenesis by PTIP-Associated Factors

PTIP 相关因子对 PPARgamma 表达和脂肪生成的调节

• 批准号: 7967794
• 负责人: Kai Ge
• 金额: $ 65.57万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967794
• 关键词: Accounting; Adipose tissue; Alternative Splicing; Cells; Complex; Defect; Diabetes Mellitus; Employee Strikes; Epigenetic Process; Fatty acid glycerol esters; Gene Expression; Generations; Histones; In Vitro; Lead; Ligands; Methylation; Methyltransferase; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Protein; Nuclear Proteins; Nuclear Receptors; Obesity; PPAR gamma; PPARgamma2; Play; Protein Isoforms; Proteins; Regulation; Risk Factors; Role; Tissues; activating transcription factor; base; in vivo; lipid biosynthesis; member; mortality; novel; novel strategies; obesity treatment; promoter; transcription factor

We have shown that in cells, a nuclear protein PTIP and a novel protein PA1 are both subunits of a Set1-like histone H3K4 methyltransferase complex (i.e. MLL3/MLL4 complex) that contains H3K4 methyltransferases MLL3 and MLL4, and the JmjC domain-containing histone H3K27 demethylase UTX (Cho, Y.-W., et al., J. Biol. Chem., 2007. 282: p. 20395-20406; Hong, S., et al., PNAS, 2007. 104: p. 18439-18444). Further, we found that histone methylation regulator PTIP is essential for the robust induction of PPARgamma and C/EBPa, the two principal adipogenic transcription factors, during adipogenesis. Accordingly, PTIP-/- cells show striking defects in adipogenesis. Thus, by regulating PPARgamma and C/EBPa expression, PTIP plays a critical role in adipogenesis (Cho, Y.W., et al., Cell Metab, 2009. 10(1): p. 27-39). Methylation on H3K4 is an activating epigenetic mark while methylation on H3K27 is a repressive one. Based on our finding that H3K4 methyltransferases MLL3/MLL4 physically associate with H3K27 demethylase UTX, we propose that by adding an activating epigenetic mark and removing a repressive one, the MLL3/MLL4 complex may use two distinct histone modifying activities to synergistically activate target gene expression. We are currently investigating the molecular mechanism by which PTIP regulates the expression of PPARgamma. Specifically, we are investigating whether the PTIP-associated H3K4 methyltransferases MLL3 and MLL4, and H3K27 demethylase UTX, are involved in the regulation of PPARgamma expression and adipogenesis.

我们已经表明，在细胞中，核蛋白PTIP和新蛋白PA 1都是Set 1样组蛋白H3 K4甲基转移酶复合物（即MLL 3/MLL 4复合物）的亚基，所述复合物含有H3 K4甲基转移酶MLL 3和MLL 4，以及含有JmjC结构域的组蛋白H3 K27去甲基酶UTX（Cho，Y. W.，例如，J. Biol. Chem.，2007. 282：第20395-20406页; Hong，S.，例如，PNAS，2007年。104：第18439-18444页）。 此外，我们发现组蛋白甲基化调节因子PTIP对于脂肪形成期间PPARgamma和C/EBPa（两种主要的脂肪形成转录因子）的稳健诱导是必不可少的。因此，PTIP-/-细胞在脂肪形成中显示出显著的缺陷。因此，通过调节PPARgamma和C/EBPa表达，PTIP在脂肪形成中起关键作用（Cho，Y.W.，例如，Cell Metab，2009. 10（1）：第27-39页）。 H3 K4上的甲基化是活化的表观遗传标记，而H3 K27上的甲基化是抑制性的。基于我们发现H3 K4甲基转移酶MLL 3/MLL 4与H3 K27去甲基酶UTX物理相关，我们提出通过添加活化表观遗传标记并去除抑制性标记，MLL 3/MLL 4复合物可以使用两种不同的组蛋白修饰活性来协同活化靶基因表达。 我们目前正在研究PTIP调节PPARgamma表达的分子机制。具体来说，我们正在研究PTIP相关的H3 K4甲基转移酶MLL 3和MLL 4，以及H3 K27去甲基化酶UTX是否参与PPARgamma表达和脂肪形成的调节。