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Transcriptional Activation by Thyroid Hormone Receptor-ß Involves Chromatin Remodeling, Histone Acetylation, and Synergistic Stimulation by p300 and Steroid Receptor Coactivators

Department of Molecular Biology and Genetics (K.C.L., W.L.K.), Cornell University, Ithaca, New York 14853; Department of Molecular and Cellular Biology (J.L., J.W.), Baylor College of Medicine, Houston, Texas 77030; Department of Pharmacology and Molecular Sciences (P.A.C.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Pharmacology (W.L.K.), Weill Medical College of Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: W. Lee Kraus, Department of Molecular Biology and Genetics, Cornell University, 465 Biotechnology Building, Ithaca, New York 14853. E-mail: wlk5{at}cornell.edu; or Jiemin Wong, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: jwong{at}bcm.tmc.edu.

Transcriptional regulation by heterodimers of thyroid hormone receptor (TR) and the 9-cis retinoid X receptor (RXR) is a highly complex process involving a large number of accessory factors, as well as chromatin remodeling. We have used a biochemical approach, including an in vitro chromatin assembly and transcription system that accurately recapitulates ligand- and activation function (AF)-2-dependent transcriptional activation by TRß/RXR heterodimers, as well as in vitro chromatin immunoprecipitation assays, to study the mechanisms of TRß-mediated transcription with chromatin templates. Using this approach, we show that chromatin is required for robust ligand-dependent activation by TRß. We also show that the binding of liganded TRß to chromatin induces promoter-proximal chromatin remodeling and histone acetylation, and that histone acetylation is correlated with increased TRß-dependent transcription. Additionally, we find that steroid receptor coactivators (SRCs) and p300 function synergistically to stimulate TRß-dependent transcription, with multiple functional domains of p300 contributing to its coactivator activity with TRß. A major conclusion from our experiments is that the primary role of the SRC proteins is to recruit p300/cAMP response element binding protein-binding protein to hormone-regulated promoters. Together, our results suggest a multiple step pathway for transcriptional regulation by liganded TRß, including chromatin remodeling, recruitment of coactivators, targeted histone acetylation, and recruitment of the RNA polymerase II transcriptional machinery. Our studies highlight the functional importance of chromatin in transcriptional control and further define the molecular mechanisms by which the SRC and p300 coactivators facilitate transcriptional activation by liganded TRß.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  RXRα  |  ERα

Coregulators:   P/CAF  |  CBP  |  p300  |  GRIP1  |  AIB1

Ligands:   Thyroid hormone

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