Histone methyltransferases catalyze site-specific deposition of methyl groups, 
enabling recruitment of transcriptional regulators. In mammals, trimethylation 
of lysine 4 in histone H3, a modification localized at the transcription start 
sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1-MLL4) 
whose specific functions are largely unknown. By using a genomic approach, we 
found that in macrophages, MLL4 (also known as Wbp7) was required for the 
expression of Pigp, an essential component of the GPI-GlcNAc transferase, the 
enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor 
synthesis. Impaired Pigp expression in Wbp7(-/-) macrophages abolished GPI 
anchor-dependent loading of proteins on the cell membrane. Consistently, loss of 
GPI-anchored CD14, the coreceptor for lipopolysaccharide (LPS) and other 
bacterial molecules, markedly attenuated LPS-triggered intracellular signals and 
gene expression changes. These data link a histone-modifying enzyme to a 
biosynthetic pathway and indicate a specialized biological role for Wbp7 in 
macrophage function and antimicrobial response.