Regulation of PPARgamma Expression and Adipogenesis by PTIP-Associated Factors

我们已经证明，在细胞中，核蛋白PTIP和新的蛋白PA1都是含有H3K4甲基转移酶ML3和MLL4的Set1样组蛋白H3K4甲基转移酶复合体(即ML3/MLL4复合体)的亚基，以及含有JmjC结构域的组蛋白H3K27去甲基酶UTx(Cho，Y.-W.，等，J.Biol)。化学，2007年。第282页：20395-20406页；洪升等，美国国家科学院院刊，2007年。此外，我们还发现，组蛋白甲基化调节因子pTIP对于脂肪形成过程中两个主要的成脂转录因子PPARγ和C/EBPA的强健诱导是必不可少的。因此，PTIP-/-细胞在成脂过程中表现出明显的缺陷。因此，通过调节PPARγ和C/EBPA的表达，PTIP在脂肪形成中起着关键作用(Cho，Y.W.等，Cell Metab，2009。10(1)：第27-39页)。 H3K4上的甲基化是一个激活的表观遗传标记，而H3K27上的甲基化是一个抑制标记。根据我们的发现，H3K4甲基转移酶MLL3/MLL4物理上与H3K27去甲基酶UTX结合，我们认为，通过增加一个激活的表观遗传标记和去除一个抑制标记，MLL3/MLL4复合体可能使用两种不同的组蛋白修饰活性来协同激活靶基因的表达。 我们目前正在研究PTIP调节PPARGamma表达的分子机制。具体地说，我们正在调查PTIP相关的H3K4甲基转移酶MLL3和MLL4以及H3K27去甲基酶UTX是否参与了PPARγ表达的调节和脂肪形成。

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.