Discovered 40 years ago, the Lec5 glycosylation mutant cell line has a complex recessive genotype and is characterized by accumulation of lipid-linked oligosaccharide assembly intermediates, reduced conversion of polyprenols to dolichols, and an unusual phenotypic dependence upon cell culture conditions such as temperature, plating density and medium quality. The heritable defect in Lec5 is unknown. Here we demonstrate an unexpected epigenetic basis for Lec5, with a surprising linkage to increased expression of homeobox genes, which in turn is associated with increased transcription of cholesterol biosynthesis genes. These results suggest testable hypotheses for the biochemical abnormalities of the Lec5 mutant.