NF-Y HAS A NOVEL ROLE IN STEROL-DEPENDENT TRANSCRIPTION OF 2 CHOLESTEROGENIC GENES

The transcription of farnesyl diphosphate (FPP) synthase is regulated up to 30-fold by the sterol status of the cell. Point mutations in a 6 -base pair ATTGGC sequence in the promoter disrupt both sterol-depende nt transcription in vivo as well as binding of the transcription facto r NF-Y in vitro. Co-transfection of cells with NF YA29, a dominant neg ative form of NF-Y, and various promoter-reporter genes specifically i nhibits the sterol-dependent regulation of FPP synthase and 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) synthase. In contrast, NP-YA29 d oes not affect the regulation of reporter genes under the control of p romoters derived from either the HMG-CoA reductase or the low density lipoprotein receptor gene. Transient expression of the 68 kDa transcri ptionally active fragment of sterol regulatory element-binding protein in cells stimulates an HMG-CoA synthase-reporter gene over 90-fold. T his induction is blocked in cells eo expressing NF-YA29. We hypothesiz e that NF-Y plays a novel role in sterol-de pendent regulation of two key genes in the cholesterol biosynthetic pathway and that this role r equires a specific interaction with the sterol regulatory element-bind ing protein or related transcription factors.