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Participation of Brahma-Related Gene 1 (BRG1)-Associated Factor 57 and BRG1-Containing Chromatin Remodeling Complexes in Thyroid Hormone-Dependent Gene Activation during Vertebrate Development

Section on Molecular Morphogenesis (R.A.H., Y.-B.S.), Laboratory of Gene Regulation and Development, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892; and Department of Basic Pharmaceutical Sciences (V.S.H.), School of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71209

Address all correspondence and requests for reprints to: Yun-Bo Shi, Laboratory of Gene Regulation and Development, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Building 18 T, Room 106, Bethesda, Maryland 20892. E-mail: Shi{at}helix.nih.gov.

Multiple cofactors and chromatin remodeling complexes have been identified to contribute to the transcriptional activation regulated by thyroid hormone receptors (TRs) in vitro. However, their role and function during development in vivo remains to be elucidated. The total dependence of amphibian metamorphosis on thyroid hormone (T₃) provides a unique vertebrate model for studying the molecular mechanism of TR function in vivo. In this study, we show that the expression of Brahma-related gene 1 (BRG1), a chromatin-remodeling enzyme, is up-regulated at the climax of Xenopus laevis metamorphosis, whereas BRG1-associated factor 57 (BAF57), a BRG1-binding protein in BRG1-containing chromatin remodeling complexes, is constitutively expressed during development. Consistently, T₃ treatment of premetamorphic tadpoles led to up-regulation of the expression of BRG1 but not BAF57. Studies using a reconstituted T₃-dependent Xenopus oocyte transcription system, where we could study TR function in the context of chromatin, revealed that BRG1 enhances the transcriptional activation by ligand-bound TRs in a dose-dependent manner, whereas a remodeling-defective BRG1 mutant inhibited the activation, suggesting that this process relies on chromatin remodeling. Additional studies showed that BAF57 interacted with BRG1 in oocytes and enhanced gene activation by TR cooperatively with BRG1 in vivo. Chromatin immunoprecipitation revealed that BAF57 was recruited to the TR-regulated promoter in the presence of TR and T₃. Together, these findings suggest a role of BRG1/BAF57-containing chromatin remodeling complexes in TR-regulated gene expression during postembryonic development.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  RXRα

Coregulators:   BRG1  |  BAF57

Ligands:   Thyroid hormone