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.

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Froimchuk, Eugene; Jang, Younghoon; Ge, Kai (2017) Histone H3 lysine 4 methyltransferase KMT2D. Gene 627:337-342
Placek, Katarzyna; Hu, Gangqing; Cui, Kairong et al. (2017) MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping. Nat Immunol 18:1035-1045
Northrup, Daniel; Yagi, Ryoji; Cui, Kairong et al. (2017) Histone demethylases UTX and JMJD3 are required for NKT cell development in mice. Cell Biosci 7:25
Lai, Binbin; Lee, Ji-Eun; Jang, Younghoon et al. (2017) MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis. Nucleic Acids Res 45:6388-6403
Zhang, Zheng; Christin, John R; Wang, Chunhui et al. (2016) Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation. Cell Rep 16:3146-3156
Ang, Siang-Yun; Uebersohn, Alec; Spencer, C Ian et al. (2016) KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation. Development 143:810-21
Faralli, Hervé; Wang, Chaochen; Nakka, Kiran et al. (2016) UTX demethylase activity is required for satellite cell-mediated muscle regeneration. J Clin Invest 126:1555-65
Benyoucef, Aissa; Palii, Carmen G; Wang, Chaochen et al. (2016) UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev 30:508-21
Yoo, Kyung Hyun; Oh, Sumin; Kang, Keunsoo et al. (2016) Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms. Mol Cell Biol 36:2108-20
Ray Chaudhuri, Arnab; Callen, Elsa; Ding, Xia et al. (2016) Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535:382-7

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