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. We have found that H3K27 demethylases UTX and Jmjd3 are dispensable for adipogenesis in vitro and in vivo. To investigate the biological function of UTX, we turned to mouse embryonic stem (ES) cells. We found that UTX controls ES cell differentiation and early embryonic development independent of H3K27 demethylase activity (Wang, C. et al.,PNAS 2012).
|Lee, Ji-Eun; Ge, Kai (2014) Transcriptional and epigenetic regulation of PPARýý expression during adipogenesis. Cell Biosci 4:29|
|Kumar, Amit; Lualdi, Margaret; Loncarek, Jadranka et al. (2014) Loss of function of mouse Pax-Interacting Protein 1-associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development. Dev Dyn 243:937-47|
|Wang, A Hongjun; Zare, Hossein; Mousavi, Kambiz et al. (2013) The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis. EMBO J 32:1075-86|
|Gong, Zihua; Cho, Young-Wook; Kim, Ja-Eun et al. (2009) Accumulation of Pax2 transactivation domain interaction protein (PTIP) at sites of DNA breaks via RNF8-dependent pathway is required for cell survival after DNA damage. J Biol Chem 284:7284-93|
|Cho, Young-Wook; Hong, SunHwa; Jin, Qihuang et al. (2009) Histone methylation regulator PTIP is required for PPARgamma and C/EBPalpha expression and adipogenesis. Cell Metab 10:27-39|