Regulation of PPARgamma Expression and Adipogenesis by PTIP-Associated Factors

我们已经证明，在细胞中，核蛋白PTIP和新蛋白PA1都是set1样组蛋白H3K4甲基转移酶复合物（即MLL3/MLL4复合物）的亚基，该复合物含有H3K4甲基转移酶MLL3和MLL4，以及含有JmjC结构域的组蛋白H3K27去甲基化酶UTX。，等。[j]。化学。, 2007年。282: p. 20395-20406；洪绍平等，《中国科学院院刊》，2007。104: 18439-18444页)。此外，我们发现组蛋白甲基化调节剂PTIP对于在脂肪形成过程中强烈诱导两种主要的脂肪生成转录因子PPARgamma和C/EBPa至关重要。因此，PTIP-/-细胞在脂肪形成中表现出明显的缺陷。因此，通过调节PPARgamma和C/EBPa的表达，PTIP在脂肪形成中起着关键作用（Cho, y.w.等，Cell Metab, 2009）。10(1)：第27-39页)。

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.