Negative Response Elements in Keratin Genes Mediate Transcriptional Repression and the Cross-talk among Nuclear Receptors

Abstract

Very little is known about the mechanisms responsible for the findings that binding of nuclear receptors (NR) to some promoter elements leads to transcriptional activation, whereas binding to others leads to repression. Case in point is the group of epidermal keratin genes and their DNA sequences responsible for repression by NR. Keratin response elements (KREs) interact with receptors for retinoic acid, thyroid hormone, and glucocorticoids. KREs, by their structure and sequence, direct the binding of retinoic acid and thyroid hormone as homodimers and glucocorticoids as monomers. Such specific DNA-receptor interactions are crucial for the repression signal of transcription. In this paper we have analyzed the interactions between the KREs and NR that lead to such repression. We have found that KREs are promoter-independent. They not only provide a docking platform for the receptors, but also play a key role in directing the receptors to bind into particular configurations and coordinating the interactions among different receptors. Both an intact KRE and an intact receptor DNA-binding domain are necessary for the regulation to occur, which emphasizes the importance of interaction between the DNA and NR for proper signaling. Furthermore, KREs allow simultaneous binding of multiple receptors, thus providing fine-tuning of transcriptional regulation. The DNA/DNA-binding domain interactions in keratin promoters exemplify tissue and gene specificity of hormone action.