The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors and belong to the nuclear hormone receptor superfamily. They form heterodimers with the retinoid X receptor and bind to specific peroxisome proliferator-response elements. The latter are direct repeat elements of two hexanucleotides with the consensus sequence TG(A/T)CCT separated by a single nucleotide spacer. Such a sequence, or a similar one, has been found in numerous PPAR-inducible genes. We developed an affinity method to isolate human genomic fragments containing binding sites for PPARs and to identify novel PPAR target genes. For this, an antibody raised against all PPAR subtypes was used. Immunoselected fragments were amplified and sequenced and one of them, ISF5148, was found to bind specifically to PPARs in gel mobility shift, supershift, and competition assays and to exhibit a down transregulation potentiality in transfection experiments under clofibrate (a PPARalpha agonist) treatment. ISF5148 was mapped by BLAST analysis 8.5 kb upstream of the human semaphorin 6B [(HSA)SEMA6B] gene. The latter encodes a member of the semaphorin family of axon guidance molecules. Expression of this gene in human glioblastoma T98G cells was strongly down regulated after treatment with clofibrate or Wy-14,643, two PPARalpha agonists. Our study establishes for the first time that PPAR activators diminish the expression of the human (HSA)SEMA6B gene. These data are relevant to the fact that PPARs are implicated in brain development, neuronal differentiation, and lipid metabolism in the central nervous system. In addition, cross talk between the peroxisome proliferator and retinoic acid pathways is suggested.