title: The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors.
abstract: Characterization of several thyroid hormone (T3), retinoic acid, and estrogen response elements has led to the identification of conserved DNA half-sites (core binding motifs). We present evidence that differences in both the relative orientation and spacing of these motifs within hormone response elements determine the distinct transcriptional responses of three members of the nuclear receptor superfamily. When separated by 3 bp, direct repeat, palindromic, and inverted palindromic arrangements of these motifs impart selective transcriptional responses to retinoic acid, estrogen, and T3 receptors, respectively. Varying the spacing between core motifs alters the specificity. Without spacing, a direct repeat of the core motif paradoxically configures the T3 receptor to confer transactivation in the absence of T3 and repression in its presence. Such an element occurs naturally in the mouse beta-thyrotropin promoter, physiologically under negative regulation by T3. The orientation and spacing of core binding motifs may thus function in concert as a code that accounts for the selective patterns of transcriptional responses of hormonally regulated promoters.
authors.affiliation: Eukaryotic Regulatory Biology Program, University of California, San Diego School of Medicine, La Jolla 92093-0648.
authors.forename: A M
authors.initials: AM
authors.lastname: Näär
authors.forename: J M
authors.initials: JM
authors.lastname: Boutin
authors.forename: S M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: V C
authors.initials: VC
authors.lastname: Yu
authors.forename: J M
authors.initials: JM
authors.lastname: Holloway
authors.forename: C K
authors.initials: CK
authors.lastname: Glass
authors.forename: M G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology*; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011960:Receptors, Estrogen / Q000502:physiology*; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D012091:Repetitive Sequences, Nucleic Acid; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D014284:Triiodothyronine / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D014212:Tretinoin