Regulation of PPARgamma and Adipogenesis by PTIP-Associated Factors

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，该复合物含有H3 K4甲基转移酶MLL 3和MLL 4（也称为ALR和MLL 2），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。一百零四：此外，我们发现组蛋白甲基化调节剂PTIP对于在脂肪形成期间PPARgamma和C/EBPa（两种主要的脂肪形成转录因子）的稳健诱导是必需的。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.，等，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相关的H3 K4甲基转移酶MLL 3和MLL 4、H3 K27去甲基化酶UTX和一种新的蛋白质PA 1是否参与PPARgamma表达和/或脂肪形成的调节。

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 (also known as ALR and MLL2), 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 whether the PTIP-associated H3K4 methyltransferases MLL3 and MLL4, H3K27 demethylase UTX, and a novel protein PA1, are involved in the regulation of PPARgamma expression and/or adipogenesis.