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This version published online on February 13, 2003
Molecular Endocrinology, doi:10.1210/me.2002-0308
A more recent version of this article appeared on May 1, 2003
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*LIOTHYRONINE

Submitted on September 4, 2002
Accepted on February 3, 2003

Transcriptional Activation by Thyroid Hormone Receptor Beta Involves Chromatin Remodeling, Histone Acetylation, and Synergistic Stimulation by p300 and SRC Coactivators

Kathleen C. Lee1, Jiwen Li1, Philip A. Cole1, Jiemin Wong1, and W. Lee Kraus1*

1 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza Houston, TX 77030, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205., Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, Equal contributors

* To whom correspondence should be addressed. E-mail: jwong{at}bcm.tmc.edu.

Transcriptional regulation by heterodimers of thyroid hormone receptor (TR) and the 9-cis retinoid acid 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 AF-2-dependent transcriptional activation by TR{beta}/RXR{alpha} heterodimers, as well as in vitro chromatin immunoprecipitation assays, to study the mechanisms of TR{beta}-mediated transcription with chromatin templates. Using this approach, we show that chromatin is required for robust ligand-dependent activation by TR{beta}. We also show that the binding of liganded TR{beta} to chromatin induces promoter-proximal chromatin remodeling and histone acetylation, and that histone acetylation is correlated with increased TR{beta}-dependent transcription. Additionally, we find that steroid receptor coactivators (SRCs) and p300 function synergistically to stimulate TR{beta}-dependent transcription, with multiple functional domains of p300 contributing to its coactivator activity with TR{beta}. A major conclusion from our experiments is that the primary role of the SRC proteins is to recruit p300/CBP to hormone-regulated promoters. Together, our results suggest a multiple step pathway for transcriptional regulation by liganded TR{beta}, 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 TR{beta}.
Key words: chromatin • chromatin remodeling • coactivators • histone acetylation • p300 • CBP • steroid receptor coactivator • transcription • thyroid hormone receptor

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  RXRα  |  ERα
Coregulators:   P/CAF  |  CBP  |  p300  |  GRIP1  |  AIB1
Ligands:   Thyroid hormone



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