NEW ASPECTS OF DNA RECOGNITION BY NUCLEAR RECEPTORS

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Our ultimate goal is to better understand how different nuclear hormone receptors recognize different target DNA sequences. Nuclear hormone receptors are ligand-regulated transcription factors, and modulate the expression of specific target genes in response to small hydrophobic hormones, such as steroids, thyroid hormones, and retinoids. The DNA recognition properties of each receptor play the critical role of defining the particular repertoire of target genes which respond to a given hormone. However, our understanding in incomplete of how the nuclear receptors, which posses generally similar zinc-finger domains, manifest the specificity necessary to recognize inherently distinct sets of target genes. Recent work by ourselves and others has revealed that: (A) regions outside of the zinc-finger domain play critical and unanticipated roles in DNA sequence-specificity, (B) nuclear hormone receptors recognize DNA binding sites not only as protein dimers, but also by novel mechanisms involving monomers and high-order oligomeric complexes, and ~ post-translational protein modifications can alter DNA recognition. These observations confirm that important elements of DNA recognition by nuclear receptors have not been previously explored, and suggest plausible mechanisms by which the specificity of different receptors for different target genes is generated and defined. We will investigate: A. How do different nuclear receptors recognize distinct DNA half- sites? B. What are the different roles of protein monomers, dimers and oligomers in DNA recognition by different members of the nuclear hormone receptor family. C. Is the mode and specificity of DNA recognition by nuclear receptors altered by post-translational modification, alternative splicing, or chromosomal translocations? Nuclear hormone receptors play central roles in metazoan homeostasis, development, and differentiation. Aberrant human receptors have been implicated in many endocrine and neoplastic diseases. Our experiments will help resolve important aspects of nuclear hormone receptor signaling and physiology, and will also contribute toward a broader comprehension of how DNA recognition specificity is achieved by other transcription factors.