DNA-BINDING PREFERENCES OF PPAR-ALPHA RXR-ALPHA - HETERODIMERS/

The regulatory elements mediating the transcriptional effects of the P eroxisome Proliferator Activated Receptor (PPAR)/Retinoid X Receptor h eterodimers consist of a direct repeat of a variant of the consensus h examer AGGTCA with an interspacing of 1 basepair (DR1), A binding site selection was performed to investigate whether any further constraint s for PPAR/RXR binding to DR1 elements exist and/or whether other high affinity binding sites for these heterodimers can be identified. One half of the recovered sequences contained two hexamers related to the consensus halfsite organised as DR1, DR2, PAL0 or as DR3, in diminishi ng order of frequency. The other binding sites consisted of three hexa mer repeats with the number of interspacing bases varying between 0 an d 7. An element with three consecutive hexamer sequences each spaced b y 1 basepair was most efficient in mediating the effects of peroxisome proliferators. The results indicate that the upstream flanking sequen ce of a DR1 differentially influences the binding of PPAR alpha/RXR al pha heterodimers and of RXR alpha homodimers. (C) 1997 Academic Press.