Developmentally Regulated N-terminal Variants of the Nuclear Receptor Hepatocyte Nuclear Factor 4[alpha] Mediate Multiple Interactions through Coactivator and Corepressor-Histone Deacetylase Complexes

• Published in: The Journal of biological chemistry 2002-11, Vol.277 (47), p.44677-44687
• Main Authors: Torres-Padilla, ME, Sladek, F M, Weiss, M C
• Format: Article
• Language: English
• ISSN: 0021-9258

To understand the mechanisms governing the regulation of nuclear receptor (NR) function, we compared the parameters of activation and repression of two isoforms of the orphan receptor hepatocyte nuclear factor (HNF) 4[alpha]. HNF4[alpha]7 and HNF4[alpha]1 differ only in their N-terminal domains, and their expression in the liver is regulated developmentally. We show that the N-terminal activation function (AF)-1 of HNF4[alpha]1 possesses significant activity that can be enhanced through interaction with glucocorticoid receptor-interacting protein 1 (GRIP-1) and cAMP response element-binding protein-binding protein (CBP). In striking contrast, HNF4[alpha]7 possesses no measurable AF-1, implying major functional differences between the isoforms. Indeed, although HNF4[alpha]1 and HNF4[alpha]7 are able to interact via AF-2 with GRIP-1, p300, and silencing mediator for retinoid and thyroid receptors (SMRT), only HNF4[alpha]1 interacts in a synergistic fashion with GRIP-1 and p300. Although both isoforms interact physically and functionally with SMRT, the repression of HNF4[alpha]7 is less robust than that of HNF4[alpha]1, which may be caused by an increased ability of the latter to recruit histone deacetylase (HDAC) activity to target promoters. Moreover, association of SMRT with HDACs enhanced recruitment of HNF4[alpha]1 but not of HNF4[alpha]7. These observations suggest that NR isoform-specific association with SMRT could affect activity of the SMRT complex, implying that selection of HDAC partners is a novel point of regulation for NR activity. Possible physiological consequences of the multiple interactions with these coregulators are discussed.