DNA conformation driven by AP‐1 triggers cell‐specific expression via a strong epithelial enhancer

We report here the characterization of the regulatory region of the human LAMA3 gene, coding for the α3A chain of laminin‐5. A 202 bp fragment is sufficient to confer epithelial‐specific expression to a thymidine kinase promoter through the cooperative effect of three AP‐1 binding sites. Remarkably, removal of the sequences located between the AP‐1 sites does not modify the promoter activity in keratinocytes but allows strong expression in fibroblasts. Replacement of the deleted sequences by non‐homologous ones fully restores the restricted enhancement in keratinocytes. Functional analysis and mutagenesis experiments demonstrate that a minimal distance between the AP‐1 sites is required for the enhancer DNA fragment to adopt a particular conformation driven by the binding of Jun–Fos heterodimers. In non‐permissive cells, this conformation leads to the anchorage of non‐DNA‐binding fibroblastic cofactors to form an inhibitory ternary complex. Therefore, our results describe for the first time an unusual conformation‐dependent epithelial‐specific enhancer.