JCB: REPORT

Covalent histone modifications regulate chromatin structure and function. Methylation of lysine residues within histones H3 and H4 by histone lysine methyltransferase complexes is one such modification. Depending on the site of the modified lysine residue and the extent of methylation (mono-, di-, or trimethylated), these modifications can lead to either activation or repression of transcription (Ng et al., 2009). Emerging evidence indicates an intimate link between abnormal histone methylation and human disease. Although histone lysine methyltransferase complexes primarily reside in the nucleus and target histones, their presence in the cytosol has been suggested (Su et al., 2005), and several nonhistone substrates have been identified (Huang and Berger, 2008). Based on our knowledge, whether a histone lysine methyltransferase complex or its subunits reside or function in the intracellular vesicular transport pathway is currently unknown. In this regard, an organellar proteomic study has detected arginine dimethylation in several Golgi proteins and revealed two putative Golgi-associated methyltransferases (Wu et al., 2004). In mammals, at least five different SET1 family methyltransferase complexes target histone H3 lysine 4 (H3K4; Ruthenburg et al., 2007; Shilatifard, 2008). Although these complexes contain distinct catalytic subunits, they share common components, including Ash2L, RbBP5, WDR5, and mammal Dpy-30 (mDpy-30). Ash2L, RbBP5, and WDR5 form a stable core complex that confers substrate specificity and controls catalytic activity (Dou et al., 2006; Steward et al., 2006). Dpy-30 was originally identified as an essential component of Caenorhabditis elegans dosage compensation machinery (Hsu et al., 1995). However, Dpy-30 mutant males also exhibit growth and development defects, indicating a general function of this protein. Subsequent studies have demonstrated that the yeast and mammalian orthologues of Dpy-30, Sdc1 (Miller et al., 2001; Roguev et al., 2001) and mDpy-30 (Hughes et al., 2004; Cho et al., 2007), respectively, Histone lysine methyltransferase complexes are essential for chromatin organization and gene regulation. Whether any of this machinery functions in membrane traffic is unknown. In this study, we report that mammal Dpy-30 (mDpy-30), a subunit of several histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) complexes, resides in the nucleus and at the trans-Golgi network (TGN). The TGN targeting of mDpy-30 is mediated by BIG1, a TGN-localized guanine nucleotide exchange factor for adenosine diphosphate ribosylation factor GTPases. Altering mDpy-30 levels changes the distribution of cation-independent mannose 6-phosphate receptor (CIMPR) without affecting that of TGN46 or transferrin receptor. Our experiments also indicate that mDpy-30 functions in the endosome to TGN transport of CIMPR and that its knockdown results in the enrichment of internalized CIMPR and recycling endosomes near cell protrusions. Much like mDpy-30 depletion, the knockdown of Ash2L or RbBP5, two other H3K4MT subunits, leads to a similar redistribution of CIMPR. Collectively, these results suggest that mDpy-30 and probably H3K4MT play a role in the endosomal transport of specific cargo proteins. A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking