Regulation of PPARgamma Expression and Adipogenesis by PTIP-Associated Factors

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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.