April 1, 2000Journal of Biological Chemistry125 citationsOpen Access

Transcriptional Activation by Hepatocyte Nuclear Factor-1 Requires Synergism between Multiple Coactivator Proteins

ESEvi SoutoglouUniversity of Sussex GPGeorge PapafotiouGerman Cancer Research Center NKNitsa KatrakiliFORTH Institute of Molecular Biology and Biotechnology

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Abstract

Hepatocyte nuclear factor-1 (HNF-1) plays an important role in the regulation of a large number of genes expressed in the liver, kidney, and pancreatic β-cells. In exploring the molecular mechanism involved in HNF-1-dependent gene activation in the in vivo chromatin context, we found that HNF-1 can physically interact with the histone acetyltransferases (HATs) CREB-binding protein (CBP), p300/CBP-associated factor (P/CAF), Src-1, and RAC3. The transcriptional activation potential of HNF-1 on a genome integrated promoter was strictly dependent on the synergistic action of CBP and P/CAF, which can independently interact with the N-terminal and C-terminal domain of HNF-1, respectively. Moreover, the HAT activity of both coactivators was important, as opposed to the selective requirement for the HAT activity of P/CAF in activation from a transiently transfected reporter. Interaction of CBP with the N-terminal domain of HNF-1 greatly increased the binding affinity for P/CAF with the C-terminal activation domain, which may represent the molecular basis for the observed functional synergism. The results support a model that involves the combined action of multiple coactivators recruited by HNF-1, which activate transcription by coupling nucleosome modification and recruitment of the general transcription machinery. Hepatocyte nuclear factor-1 (HNF-1) plays an important role in the regulation of a large number of genes expressed in the liver, kidney, and pancreatic β-cells. In exploring the molecular mechanism involved in HNF-1-dependent gene activation in the in vivo chromatin context, we found that HNF-1 can physically interact with the histone acetyltransferases (HATs) CREB-binding protein (CBP), p300/CBP-associated factor (P/CAF), Src-1, and RAC3. The transcriptional activation potential of HNF-1 on a genome integrated promoter was strictly dependent on the synergistic action of CBP and P/CAF, which can independently interact with the N-terminal and C-terminal domain of HNF-1, respectively. Moreover, the HAT activity of both coactivators was important, as opposed to the selective requirement for the HAT activity of P/CAF in activation from a transiently transfected reporter. Interaction of CBP with the N-terminal domain of HNF-1 greatly increased the binding affinity for P/CAF with the C-terminal activation domain, which may represent the molecular basis for the observed functional synergism. The results support a model that involves the combined action of multiple coactivators recruited by HNF-1, which activate transcription by coupling nucleosome modification and recruitment of the general transcription machinery. hepatocyte nuclear factor CREB-binding protein histone acetyltransferase p300/CBP-associated factor receptor associated coactivator 3 steroid receptor coactivator-1 amino acid(s) nucleotide(s) glutathioneS-transferase C-terminal activation domain trichostatin A Tissue-specific expression of hepatic genes is accomplished by the concerted action of a small number of liver-enriched regulatory proteins, including the HNF-11 (1.Bach I. Mattei M.G. Cereghini S. Yaniv M. Nucleic Acids Res. 1991; 19: 3553-3559Crossref PubMed Scopus (89) Google Scholar, 2.Baumhueter S. Mendel D.B. Conley P.B. Kuo C.J. Turk C. Graves M.K. Edwards C.A. Courtois G. Crabtree G.R. Genes Dev. 1990; 4: 372-379Crossref PubMed Scopus (178) Google Scholar, 3.Frain M. Swart G. Monaci P. Nicosia A. 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A. 1991; 88: 3807-3811Crossref PubMed Scopus (142) Google Scholar). This pattern is achieved by a complex cross-regulatory network that has been postulated to determine the hepatic phenotype (9.Duncan S.A. Navas M.A. Dufort D. Rossant J. Stoffel M. Science. 1998; 281: 692-695Crossref PubMed Scopus (292) Google Scholar, 10.Kuo C.J. Conley P.B. Chen L. Sladek F.M. Darnell Jr., J.E. Crabtree G.R. Nature. 1992; 355: 457-461Crossref PubMed Scopus (367) Google Scholar, 11.Tian J.M. Schibler U. Genes Dev. 1991; 5: 2225-2234Crossref PubMed Scopus (155) Google Scholar). HNF-1 plays a central role in the coordination of this network, via positive regulation of a large number of downstream target genes (12.Tronche F. Yaniv M. BioEssays. 1992; 14: 579-587Crossref PubMed Scopus (193) Google Scholar) and via negative regulation of genes activated by HNF-4, including the HNF-1 gene itself (13.Kritis A.A. Ktistaki E. Barda D. Zannis V.I. Talianidis I. Nucleic Acids Res. 1993; 21: 5882-5889Crossref PubMed Scopus (51) Google Scholar, 14.Ktistaki E. Talianidis I. Science. 1997; 277: 109-112Crossref PubMed Scopus (108) Google Scholar). The key role of HNF-1 in nonhepatic tissues, such as in pancreatic β-cells and the kidney, has been recently highlighted by the complex phenotype of HNF-1−/− mice (15.Pontoglio M. Barra J. Hadchouel M. Doyen A. Kress C. Bach J.P. Babinet C. Yaniv M. Cell. 1996; 84: 575-585Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar, 16.Lee Y.H. Sauer B. Gonzalez F.J. Mol. Cell. Biol. 1998; 18: 3059-3068Crossref PubMed Scopus (224) Google Scholar, 17.Pontoglio M. Sreenan S. Roe M. Pugh W. Ostrega D. Doyen A. Pick A.J. Baldwin A. Velho G. Froguel P. Levisetti M. Bonner-Weir S. Bell G.I. Yaniv M. Polonsky K.S. J. Clin. 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Cell. 1989; 59: 145-157Abstract Full Text PDF PubMed Scopus (337) Google Scholar). Two features distinguish HNF-1 from other homeodomain transcription factors: it contains an extra 21-amino acid loop within the DNA-binding domain and dimerizes via the N-terminal dimerization domain (2.Baumhueter S. Mendel D.B. Conley P.B. Kuo C.J. Turk C. Graves M.K. Edwards C.A. Courtois G. Crabtree G.R. Genes Dev. 1990; 4: 372-379Crossref PubMed Scopus (178) Google Scholar, 3.Frain M. Swart G. Monaci P. Nicosia A. Stampfli S. Frank R. Cortese R. Cell. 1989; 59: 145-157Abstract Full Text PDF PubMed Scopus (337) Google Scholar). The dimerization domain can associate with DcoH (19.Mendel D.B. Khavari P.A. Conley P.B. Graves M.K. Hansen L.P. Admon A. Crabtree G.R. Science. 1991; 254: 1762-1767Crossref PubMed Scopus (185) Google Scholar), an 11-kDa protein that has been suggested to be involved in dimer stabilization (20.Johnen G. Kaufman S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13469-13474Crossref PubMed Scopus (24) Google Scholar). The C-terminal part of HNF-1 contains at least three regions, ADI, ADII, and ADIII, that have been shown to be indispensable for transcription activation (3.Frain M. Swart G. Monaci P. Nicosia A. Stampfli S. Frank R. Cortese R. Cell. 1989; 59: 145-157Abstract Full Text PDF PubMed Scopus (337) Google Scholar, 12.Tronche F. Yaniv M. BioEssays. 1992; 14: 579-587Crossref PubMed Scopus (193) Google Scholar). Recent studies on the regulatory region of phenylalanine hydroxylase (21.Pontoglio M. Faust D.M. Doyen A. Yaniv M. Weiss M.C. Mol. Cell. Biol. 1997; 17: 4948-4956Crossref PubMed Google Scholar) and the α1-antitrypsin-CBG gene cluster (22.Rollini P. Fournier R.E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10308-10313Crossref PubMed Scopus (39) Google Scholar) using an HNF-1−/− mouse model and hepatoma cell variants, respectively, raised the possibility of the potential role of HNF-1 in controlling chromatin remodeling. One route to the transcription factor-dependent chromatin modification is the recruitment of coactivators that possess intrinsic histone acetyltransferase activities. Several such intermediary proteins, including GCN5 (23.Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1273) Google Scholar), CBP (24.Kamei Y. Xu L. Heinzel T. Torchia J. Kurokawa R. Gloss B. Lin S.C. Heyman R.A. Rose D.W. Glass C.K. Rosenfeld M.G. Cell. 1996; 85: 403-414Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar, 25.Lundblad J.R. Kwok R.P. Laurance M.E. Harter M.L. Goodman R.H. Nature. 1995; 374: 85-88Crossref PubMed Scopus (529) Google Scholar), P/CAF (26.Yang X.J. Ogryzko V.V. Nishikawa J. Howard B.H. Nakatani Y. Nature. 1996; 382: 319-324Crossref PubMed Scopus (1306) Google Scholar), and the p160 family of proteins (Src-1 (27.Onate S.A. Tsai S.Y. Tsai M.J. O'Malley B.W. Science. 1995; 270: 1354-1357Crossref PubMed Scopus (2039) Google Scholar) and ACTR/RAC3 (28.Chen H. Lin R.J. Schiltz R.L. Chakravarti D. Nash A. Nagy L. Privalsky M.L. Nakatani Y. Evans R.M. Cell. 1997; 90: 569-580Abstract Full Text Full Text PDF PubMed Scopus (1250) Google Scholar, 29.Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1518) Google Scholar)) have been shown to interact with a wide variety of transcription factors and to stimulate transcription, acting as bridging proteins between activators and the general transcription factors and via acetylation of the surrounding nucleosomes to allow greater accessibility of other factors to the promoter (23.Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1273) Google Scholar, 26.Yang X.J. Ogryzko V.V. Nishikawa J. Howard B.H. Nakatani Y. 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The of CBP to P/CAF has been observed in the CBP domain of HNF-1, only expressed CBP was in the binding CBP to the N-terminal region of HNF-1 may the binding of P/CAF to the C-terminal activation domain of HNF-1, we using which contains the P/CAF with HNF-1 both in the and of the of the was the P/CAF complex was only in the of CBP This was observed only in the of the HNF-1 protein and not with the protein HNF-1 the P/CAF In in this CBP the binding of P/CAF to the HNF-1 domain, which may be to between HNF-1 and CBP for with P/CAF The that binding of CBP to the N-terminal region of HNF-1 the affinity of P/CAF binding to the C-terminal domain, and the increased of this complex may be for the synergistic activation observed in the we between CBP and P/CAF is important for HNF-1-dependent activation in hepatic of CBP P/CAF in cells in a and a of of both CBP and P/CAF HNF-1 activity that CBP and P/CAF may with HNF-1 in hepatic The of at least of with with The can be by the levels of CBP and P/CAF in that both CBP and P/CAF important for transcription in hepatic we with and in with CBP with P/CAF both Bannister A.J. 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BioEssays. 1992; 14: 579-587Crossref PubMed Scopus (193) Google Scholar). studies important with to the of HNF-1 on and with other transcription factors not HNF-1 be involved in the activation of these genes in vivo chromatin this suggested that the mechanism of target gene expression in vivo HNF-1-dependent of of the phenylalanine hydroxylase promoter between and HNF-1−/− mice (21.Pontoglio M. Faust D.M. Doyen A. Yaniv M. Weiss M.C. Mol. Cell. Biol. 1997; 17: 4948-4956Crossref PubMed Google Scholar). studies on the α1-antitrypsin-CBG gene cluster have shown of in hepatoma on the expression of HNF-4 and HNF-1 (22.Rollini P. Fournier R.E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10308-10313Crossref PubMed Scopus (39) Google Scholar). In both a positive between chromatin and target gene expression was The raised the of the in chromatin an of HNF-1 via the activation of other HNF-1 be involved in chromatin remodeling. The results in this of HNF-1 with proteins intrinsic nucleosome the molecular basis for the found that P/CAF, Src-1, and can independently interact with functional of HNF-1 and in a synergistic The molecular basis of this in the of the coactivators to interact with The of such for the recruitment of multiple coactivators by various transcription factors has been E. Torchia J. Rose D.W. Xu L. Kurokawa R. Glass C.K. Rosenfeld M.G. Science. 1998; PubMed Scopus Google Scholar, R. D. C. Xu L. Torchia J. Rosenfeld M.G. Glass C.K. Science. 1998; PubMed Scopus Google Scholar, H. Chen J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Zhou N. R. D.M. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). in the of nuclear P/CAF and to a molecular for the recruitment of CBP and to a coactivator complex E. Torchia J. Rose D.W. Xu L. Kurokawa R. Glass C.K. Rosenfeld M.G. Science. 1998; PubMed Scopus Google Scholar, R. D. C. Xu L. Torchia J. Rosenfeld M.G. 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Biol. 1999; 19: PubMed Google Scholar), the HAT activity of CBP is for E. Talianidis I. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar, E. Torchia J. Rose D.W. Xu L. Kurokawa R. Glass C.K. Rosenfeld M.G. Science. 1998; PubMed Scopus Google Scholar). In it has been shown that the can the of CBP by HAT activity in a V. Kurokawa R. E. Rose D.W. Glass C.K. Rosenfeld M.G. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). In the of HNF-1 we found that the HAT activity of both CBP and P/CAF important for high levels of activation on genome integrated promoter as opposed to selective requirement for the HAT activity of P/CAF in the transiently transfected reporter. Moreover, in the integrated promoter context, only the combined action of CBP and P/CAF on HNF-1 was to high transcription, CBP P/CAF only that in the of the promoter is a chromatin that a for transcription, with that by the on transiently transfected which may not be in a of nucleosomes P. Science. 1992; PubMed Scopus Google Scholar). The requirement for multiple HAT with and (26.Yang X.J. Ogryzko V.V. Nishikawa J. Howard B.H. Nakatani Y. Nature. 1996; 382: 319-324Crossref PubMed Scopus (1306) Google Scholar, 29.Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1518) Google Scholar, 32.Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2355) Google Scholar) be to the increased of the chromatin by the integrated of proteins in the coactivator complex that possess HAT (Src-1 and (28.Chen H. Lin R.J. Schiltz R.L. Chakravarti D. Nash A. Nagy L. Privalsky M.L. Nakatani Y. Evans R.M. Cell. 1997; 90: 569-580Abstract Full Text Full Text PDF PubMed Scopus (1250) Google Scholar, 33.Spencer T.E. Jenster G. Burcin M.M. Allis C.D. Zhou J. Mizzen C.A. N.J. S.A. Tsai S.Y. Tsai M.J. O'Malley B.W. Nature. 1997; PubMed Scopus Google Scholar) may not be to the In this we a HNF-1-dependent promoter to from the action of other DNA-binding This has to and the of multiple coactivator proteins, which may a to the complex mechanism involved in HNF-1-dependent chromatin and gene In the of regulatory regions, the of nucleosomes may the of other transcription which may in the and of the coactivator complex in a In the expression levels of the coactivators in a cell may a role in the of the coactivator complex recruited by In with the of of coactivators observed in this we that the of the coactivator complex on HNF-1 may have a on promoter and the of HNF-1 in the transcriptional activity of a gene in a cell to J. D. R. T. B. W. Y. J. D. and Tsai for the P. for and of the

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