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Thyroid Hormone-Regulated Target Genes Have Distinct Patterns of Coactivator Recruitment and Histone Acetylation

Department of Medicine, Johns Hopkins Bayview Medical Center (P.M.Y., X.X.), Johns Hopkins University, Baltimore, Maryland 21224; Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Y.L.), Bethesda, Maryland 20892; and Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (J.D.F.), Piscataway, New Jersey 08854

Address all correspondence and requests for reprints to: Dr. Paul M. Yen, Endocrinology Division, Department of Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Room B114, Baltimore, Maryland 21224. E-mail: pyen3{at}jhmi.edu.

Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements of target genes. Upon ligand binding, they recruit coactivator complexes that increase histone acetylation and recruit RNA polymerase II (Pol II) to activate transcription. Recent studies suggest that nuclear receptors and coactivators may have temporal recruitment patterns on hormone response elements, yet little is known about the nature of the patterns at multiple endogenous target genes. We thus performed chromatin immunoprecipitation assays to investigate coactivator recruitment and histone acetylation patterns on the thyroid hormone response elements of four endogenous target genes (GH, sarcoplasmic endoplasmic reticulum calcium-adenosine triphosphatase, phosphoenolpyruvate carboxykinase, and cholesterol 7-hydroxylase) in a rat pituitary cell line that expresses TRs. We found that TRß, several associated coactivators (steroid receptor coactivator-1, glucocorticoid receptor interacting protein-1, and TR-associated protein 220), and RNA Pol II were rapidly recruited to thyroid hormone response elements as early as 15 min after T₃ addition. When the four target genes were compared, we observed differences in the types and temporal patterns of recruited coactivators and histone acetylation. Interestingly, the temporal pattern of RNA Pol II was similar for three genes studied. Our findings suggest that thyroid hormone-regulated target genes may have distinct patterns of coactivator recruitment and histone acetylation that may enable highly specific regulation.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ

Coregulators:   TRAP220  |  SRC-1  |  GRIP1

Ligands:   Thyroid hormone

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