Androgen activation of the folate receptor α gene through partial tethering of the androgen receptor by C/EBPα

The folate receptor α (FRα) is critical for normal embryonic and fetal development. The receptor has a relatively narrow tissue specificity which includes the visceral endoderm and the placenta and mediates delivery of folate, inadequacy of which results in termination of pregnancy or developmental defects. We have previously reported that the FRα gene is negatively and directly regulated by estrogen and positively but indirectly by progesterone and glucocorticoid. To further investigate hormonal control of this gene and in view of the growing evidence for the importance of the androgen receptor (AR) in endometrial and placental functions, we examined the response of the FRα gene to androgen. Here we demonstrate that the FRα gene is directly activated by androgen. The P4 promoter of the FRα gene is the target of hormone-dependent activation by the androgen receptor (AR) in a manner that is co-activator-dependent. The site of functional association of AR in the FRα gene maps to a 35 bp region occurring ∼1500 bp upstream of the target promoter. The functional elements within this region are an androgen response element (ARE) half-site and a non-canonical C/EBP element that cooperate to recruit AR in a manner that is dependent on the DNA-bound C/EBPα. Since the placenta is rich in C/EBPα, the findings underscore the multiplicity of mechanisms by which the FRα gene is under the exquisite control of steroid hormones.