Histone modification plays important roles in many biological processes such as 
development and carcinogenesis. Methylation of histone H3 lysine 4 (H3K4) is 
commonly associated with transcriptional activation of genes. H3K4 methylation 
in mammalian cells is carried out by COMPASS (complex of proteins associated 
with Set1)-like complexes that are composed of catalytic subunits such as MLL1 
(mixed-lineage leukaemia 1) and multiple regulatory subunits in which WDR5 (WD40 
repeat-containing protein 5), RBBP5 (retinoblastoma-binding protein 5), ASH2 
(absent, small or homoeotic discs 2) and DPY30 [constituting the WRAD 
sub-complex (WDR5-ASH2-RBBP5-DPY30 complex)] are the major ones shared from 
yeast to metazoans. We report, in the present paper, a new mode of spatial 
regulation of H3K4 methyltransferase complexes. PAQR3 (progestin and adipoQ 
receptors member 3), a tumour suppressor specifically localized in the Golgi 
apparatus, negatively regulates H3K4 trimethylation (H3K4me3) in mammalian 
cells. Consistently, HOXC8 and HOXA9 gene expression was negatively regulated by 
PAQR3 expression levels. Hypoxia-induced H3K4me3 was augmented by PAQR3 
knockdown and suppressed by PAQR3 overexpression in AGS gastric cancer cells. 
PAQR3 was able to interact directly or indirectly with the four members of the 
WRAD sub-complex and tether them to the Golgi apparatus, accompanied by 
reduction in histone methyltransferase activity in the nucleus. PAQR3 also 
interfered with the interaction of WDR5 with the C-terminus of MLL1 (C-ter). 
Collectively, our study indicates that PAQR3 negatively modulates H3K4 
methylation via altering the subcellular compartmentalization of the core 
regulatory subunits of the COMPASS-like complexes in mammalian cells.