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  • The EMBO Journal (2006) 25, 3966 - 3974
  • doi:10.1038/sj.emboj.7601280

Published online: 17 August 2006

The N-CoR complex enables chromatin remodeler SNF2H to enhance repression by thyroid hormone receptor

Theresa Alenghat, Jiujiu Yu and Mitchell A Lazar

  1. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Correspondence to:

Mitchell A Lazar, Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Pennsylvania School of Medicine, 611 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-6149, USA. Tel.: 215 898 0198; Fax: 215 898 5408; E-mail: lazar@mail.med.upenn.edu

Received 8 March 2006; Accepted 21 July 2006

Unliganded thyroid hormone receptor (TR) actively represses transcription via the nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex. Although transcriptional activation by liganded receptors involves chromatin remodeling, the role of ATP-dependent remodeling in receptor-mediated repression is unknown. Here we report that SNF2H, the mammalian ISWI chromatin remodeling ATPase, is critical for repression of a genomically integrated, TR-regulated reporter gene. N-CoR and HDAC3 are both required for recruitment of SNF2H to the repressed gene. SNF2H does not interact directly with the N-CoR/HDAC3 complex, but binds to unacetylated histone H4 tails, suggesting that deacetylase activity of the corepressor complex is critical to SNF2H function. Indeed, HDAC3 as well as SNF2H are required for nucleosomal organization on the TR target gene. Consistent with these findings, reduction of SNF2H induces expression of an endogenous TR-regulated gene, dio1, in liver cells. Thus, although not apparent from studies of transiently transfected reporter genes, gene repression by TR involves the targeting of chromatin remodeling factors to repressed genes by the HDAC activity of nuclear receptor corepressors.

  • Keywords:

    • chromatin,
    • HDAC,
    • nuclear receptor,
    • repression,
    • SNF2H