Nuclear receptors (NRs) function as transcription factors that respond to cellular signals to initiate new gene expression programs (King-Jones and Thummel, 2005) and have essential roles in embryonic development, growth and differentiation. NRs

INTRODUCTION Nuclear receptors (NRs) function as transcription factors that respond to cellular signals to initiate new gene expression programs (King-Jones and Thummel, 2005) and have essential roles in embryonic development, growth and differentiation. NRs collaborate with co-factors (>300) that provide important enzymatic and regulatory functions (Lonard and O’Malley, 2007; Lonard and O’Malley, 2006). Co-factors can be activators or repressors and are typically recruited to gene promoters through associations with receptors (Bulynko and O’Malley, 2011). Some co-factors direct changes in the epigenetic environment of target genes by direct covalent chromatin modification or nucleosome remodeling. Co-activators are recruited in a ligand-dependent manner, whereas unliganded receptors often associate with corepressors. Co-activators exist in large complexes required for the transcription of genes that are regulated by at least 48 vertebrate NRs, including retinoic acid receptor (RAR) (Goo et al., 2003; Lee et al., 2006), estrogen receptor (ER) (Mo et al., 2006), liver-Xreceptor (LXR) (Lee, S. et al., 2008), farnesoid-X-receptor (FXR) (Kim et al., 2009), as well as a co-activator for p53 (Lee et al., 2009). Disruptions of both NRs and their co-regulators have been linked to many cancers and developmental disorders (Lonard et al., 2007; Sonoda et al., 2008). Hormone signaling pathways in Drosophila melanogaster rely on two primary hormones, the steroid hormone 20hydroxyecdysone (20HE) and sesquiterpenoid juvenile hormone (JH; JHE – FlyBase), and 18 receptors representing all major conserved nuclear receptor subfamilies (King-Jones and Thummel, 2005). Drosophila Ecdysone Receptor (EcR) is an FXR/LXR ortholog, whereas its heterodimeric partner Ultraspiracle (USP) is an RXR ortholog. Drosophila Trithorax-related (TRR) is a co-activator of EcRUSP. TRR is a histone lysine methyltransferase (HMT) that trimethylates histone 3 onlysine 4 (H3K4me3) and TRR functions are essential for activating ecdysone-regulated genes (Sedkov et al., 2003). TRR is closely related to another Drosophila protein, Trithorax (TRX), which regulates homeotic (Hox) gene expression through similar methyltransferase activity (Schuettengruber et al., 2007; Simon and Tamkun, 2002). The mammalian counterparts of TRR are MLL2 (also known as ALR or MLL4) and MLL3 (also known as HALR). MLL2 and MLL3 are enormous (5537 aa and 4911 aa, respectively), with multiple conserved domains, including histone methyltransferase (SET domain), five plant homeodomain (PHD) zinc fingers, an HMG-I binding motif, LXXLL NR binding motifs and FY-rich regions (Prasad et al., 1997). Through the SET domain, both MLL2 and MLL3 directly methylate histone H3 to mediate transcription activation (Issaeva et al., 2007; Vicent et al., 2011). MLL2 and MLL3 are components of large SET1/COMPASS-like co-activator complexes (Eissenberg and Shilatifard, 2010; Miller et al., 2001; Nagy et al., 2002) that are required for NR-directed gene regulation (Goo et al., 2003; Issaeva et al., 2007; Lee et al., 2006; Mo et al., 2006). These complexes have important human disease connections, including developmental disorders and cancers. MLL2 1Oncology Institute, 2Department of Medicine, 3Department of Pathology, Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA.