HNF1/TCF2 mutations impair transactivation potential through altered co-regulator recruitment
Authors: Elena Barbacci1; Angeliki Chalkiadaki2; Christelle Masdeu1; Cécile Haumaitre1; Ludmilla Lokmane1; Chantal Loirat3; Sylvie Cloarec4; Iannis Talianidis2; Christine Bellanne-Chantelot5; Silvia Cereghini1
Source: Human Molecular Genetics, Volume 13, Number 24, 15 December 2004 , pp. 3139-3149(11)
Publisher: Oxford University Press
Abstract:Mutations in the HNF1 gene, encoding the dimeric POU-homeodomain transcription factor HNF1 (TCF2 or vHNF1), cause various phenotypes including maturity onset diabetes of the young 5 (MODY5), and abnormalities in kidney, pancreas and genital tract development. To gain insight into the molecular mechanisms underlying these phenotypes and into the structure of HNF1, we functionally characterized eight disease-causing mutations predicted to produce protein truncations, amino acids substitutions or frameshift deletions in different domains of the protein. Truncated mutations, retaining the dimerization domain, displayed defective nuclear localization and weak dominant-negative activity when co-expressed with the wild-type protein. A frameshift mutation located within the C-terminal QSP-rich domain partially reduced transcriptional activity, whereas selective deletion of this domain abolished transactivation. All five missense mutations, which concern POU-specific and homeodomain residues, were correctly expressed and localized to the nucleus. Although having different effects on DNA-binding capacity, which ranged from complete loss to a mild reduction, these mutations exhibited a severe reduction in their transactivation capacity. The transcriptional impairment of those mutants, whose DNA-binding activity was weakly or not affected, correlated with the loss of association with one of the histone-acetyltransferases CBP or PCAF. In contrast to wild-type HNF1, whose transactivation potential depends on the synergistic action of CBP and PCAF, the activity of these mutants was not increased by the synergistic action of these two coactivators or by treatment with the specific histone-deacetylase inhibitor TSA. Our findings suggest that the complex syndrome associated with HNF1-MODY5 mutations arise from either defective DNA-binding or transactivation function through impaired coactivator recruitment.
Document Type: Research article
Affiliations: 1: Biologie du Développement, UMR 7622, CNRS, Université Pierre et Marie Curie, 9 quai St Bernard, 75005 Paris, France, 2: Institute of Molecular Biology and Biotechnology, FORTH 1527, Vassilika Vouton, 711 10 Herakleion, Crete, Greece, 3: Hôpital Robert-Debré, Service de Néphrologie, 48 bd Serrurier, 75019 Paris, France, 4: Hôpital de Tours, Centre Hospitalier Universitaire, 49 bd Beranger, 37044 Tours Cedex, France and 5: Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
Publication date: 2004-12-15
- Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.
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- By this author: Elena Barbacci ; Angeliki Chalkiadaki ; Christelle Masdeu ; Cécile Haumaitre ; Ludmilla Lokmane ; Chantal Loirat ; Sylvie Cloarec ; Iannis Talianidis ; Christine Bellanne-Chantelot ; Silvia Cereghini