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和新型蛋白质PA1都是SET1样组蛋白H3K4 H3K4甲基转移酶复合酶复合物（即MLL3/MLL4复合物）的亚基，其中含有H3K4甲基转移酶MLL3和MLL4和MLL4，以及JMJC域含有JMJC域的含有JMJC的Hythase Hythase J. Biol。 此外，我们发现在脂肪形成过程中，组蛋白甲基化调节剂PTIP对于强诱导Ppargamma和C/EBPA（两个主要的脂肪生成转录因子）至关重要。因此，PTIP - / - 细胞在脂肪形成中显示出明显的缺陷。因此，通过调节ppargamma和c/eBPA的表达，PTIP在脂肪形成中起着至关重要的作用（Cho，Y.W.，et al。，Cell Metab，2009。10（1）：第27-39页）。 H3K4上的甲基化是一种激活的表观遗传标记，而H3K27上的甲基化是一种抑制性。基于我们的发现，H3K4甲基转移酶MLL3/MLL4物理与H3K27脱甲基酶UTX相关，我们提出，通过添加激活的表观遗传标记并删除抑制性脱甲基，MLL3/MLL4复合物可以使用两个不同的组蛋白改性活性来协调性激活目标基因。 我们目前正在研究PTIP调节ppargamma表达的分子机制。具体而言，我们正在研究与PTIP相关的H3K4甲基转移酶MLL3和MLL4以及H3K27脱甲基酶UTX是否参与PPARGAMMA表达和脂肪形成的调节。