HNF1 β/TCF2 mutations impair transactivation potential through altered co-regulator recruitment

Barbacci, E; Chalkiadaki, Angeliki; Masdeu, Christelle; Haumaitre, Cécile; Lokmane, Ludmilla; Loirat, Chantal; Cloarec, Sylvie; Talianidis, Iannis; Bellanné‐Chantelot, Christine; Cereghini, Silvia

doi:10.1093/hmg/ddh338

Cited by 92 publications

(83 citation statements)

References 36 publications

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“…We have reported that this difference may be caused by the difference in DNA binding affinity (Kitanaka et al 2004). The dominant-negative effect of R177X mutant on wildtype HNF-1b has also been reported to differ with cells and promoters (Tomura et al 1999, Barbacci et al 2004, Gu et al 2004. From these observations, we consider that analyses of the intended native promoters in combination with wild-type HNF-1b and HNF-1a are essential to investigate the function of HNF-1b mutants.…”

Section: Discussionmentioning

confidence: 91%

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

Kitanaka

Sato

Igarashi

2007

Journal of Endocrinology

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Mutations in hepatocyte nuclear factor-1b (HNF-1b) lead to type 5 maturity-onset diabetes of the young (MODY5). Moreover, mutations in the HNF-1b gene might cause multiorgan abnormalities including renal diseases, genital malformations, and abnormal liver function. The objective of this study was to investigate the molecular mechanism of diabetes mellitus, intrauterine growth retardation, and cholestasis observed in MODY5 patients. We analyzed the transactivity of wild-type and three mutant HNF-1b on native human insulin, IGF-I, and multidrug resistance protein 2 (MRP2) promoters in combination with HNF-1a, using a reporter-assay system in transiently transfected mammalian cells. In the human insulin gene promoter, we found that the cooperation of HNF-1a and HNF-1b is prominent. Absence of this cooperation was observed in all of the HNF-1b mutants. In the human IGF-I and MRP2 promoters, we found that the HNF-1b His153Asn (H153N) mutant had a mutant-specific repressive effect on both HNF-1a and wild-type HNF-1b transactivity. Absence of the cooperation of HNF-1b mutants with HNF-1a in the human insulin gene promoter might be one cause of defective insulin secretion. The H153N mutantspecific repression of HNF-1a and HNF-1b transactivity in human IGF-I and MRP2 promoters might explain the casespecific clinical features of growth retardation and cholestasis observed only in early infancy. We found differential property of HNF-1a/HNF-1b activity and the effect of HNF-1b mutants by the promoters. We consider that analyses of HNF1b mutants on the intended human native promoters in combination with HNF-1a may be useful in investigating the molecular mechanisms of the various features in MODY5.

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Section: Discussionmentioning

confidence: 91%

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

Kitanaka

Sato

Igarashi

2007

Journal of Endocrinology

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“…In addition to these phenotypes, variable levels of pancreas atrophies have recently been associated with different TCF2 mutations (19,20). Remarkably, we have recently identified a severe pancreas hypoplasia in two fetuses carrying previously undescribed mutations in the TCF2 gene (A. L. Delezoide, C.H., and S.C., unpublished results).…”

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confidence: 75%

Lack of TCF2/vHNF1 in mice leads to pancreas agenesis

Haumaitre

Barbacci

Jenny

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

238

221

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Heterozygous mutations in the human POU-homeobox TCF2 (vHNF1, HNF1␤) gene are associated with maturity-onset diabetes of the young, type 5, and abnormal urogenital tract development. Recently, pancreas atrophies have been reported in several maturity-onset diabetes of the young type 5 patients, suggesting that TCF2 is required not only for adult pancreas function but also for its normal development. Tcf2-deficient mice die before gastrulation because of defective visceral endoderm formation. To investigate the role of this factor in pancreas development, we rescued this early lethality by tetraploid aggregation. We show that TCF2 has an essential function in the first steps of pancreas development, correlated with its expression domain that demarcates the entire pancreatic buds from the earliest stages. Lack of TCF2 results in pancreas agenesis by embryonic day 13.5. At earlier stages, only a dorsal bud rudiment forms transiently and expresses the transcription factors Ipf1 and Hlxb9 but lacks the key transcription factor involved in the acquisition of a pancreatic fate, Ptf1a, as well as all endocrine precursor cells. Regional specification of the gut also is perturbed in Tcf2 ؊/؊ embryos as manifested by ectopic expression of Shh and lack of Ihh and Ipf1 in the posterior stomach and duodenum. Our results highlight the requirement of Tcf2 for ensuring both accurate expression of key regulator molecules in the stomach-duodenal epithelium and proper acquisition of the pancreatic fate. This study provides further insights into early molecular events controlling pancreas development and may contribute to the development of cell-replacement strategies for diabetes.diabetes MODY5 ͉ homeodomain transcription factor ͉ pancreas development ͉ gut regionalization ͉ tetraploid aggregation I n mammals, the pancreas emerges as ventral and dorsal evaginations from the foregut-midgut junction that subsequently fused to form a complex organ. The signaling molecule Sonic Hedgehog (SHH) demarcates a molecular boundary between the prepancreatic endoderm and adjacent stomach and duodenal anlagen and exerts an inhibitory action on pancreas development (1-3). Genetic studies in mice have identified a hierarchical regulatory network involved in pancreas morphogenesis, with significant and sequential differences between ventral and dorsal pancreas. In the mouse, the dorsal bud appears at embryonic day 9.5 (E9.5) concomitantly with the first differentiated glucagon-producing cells. The homeobox gene Ipf1(Pdx1) is expressed before and during this budding, and all pancreatic cell types derive from IPF1 ϩ progenitors (4, 5). However, in Ipf1-deficient mice, pancreas development is arrested after budding (6, 7), implying that other factors promote pancreas specification. Recently, the transcription factor Ptf1a (P48) has been shown to be essential for the acquisition of a pancreatic fate by undifferentiated ventral foregut endoderm, being required for the specification of the ventral pancreas and robust outgrowth of the dorsal bud. In its a...

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“…These results might indicate that there is a relatively high threshold for sufficient transcription, or alternatively, the activation level could be gene-specific and the expression of essential genes is below the level needed for proper development and function with the mutant. It has been reported that the R295H mutant exhibited target-specific effects of activation in which the transactivation potential of R295H on the HNF4α promoter reached to wild-type transactivation level, while transactivation of either Afp or albumin promoter by this mutant were barely detectable (49). In other studies, the corresponding mutants R263C/L in HNF1α showed greatly reduced DNA binding activity as a result of these more drastic substitutions (52,53).…”

Section: Disease-related Mutationsmentioning

confidence: 91%

“…These effects on transcriptional activity could be gene-specific or synergistic partner-dependent. It has been reported that the effects on transcription of some of these mutants, especially those that do not affect or only weakly affect the DNA-binding activity, correlate with the loss of association with the transcriptional coregulators such as CBP or PCAF (49). Thus, even though the molecular bases of the functional disruptions have been elucidated, other mechanistic details that might be exploited for intervention await additional studies.…”

Section: Disease-related Mutationsmentioning

confidence: 99%

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,

2007

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HNF1β is an atypical POU transcription factor that participates in a hierarchical network of transcription factors controlling the development and proper function of vital organs such as liver, pancreas, and kidney. Many inheritable mutations on HNF1β are the monogenic causes of diabetes and several kidney diseases. To elucidate the molecular mechanism of its function and the structural basis of mutations, we have determined the crystal structure of human HNF1β DNA binding domain in complex with a high-affinity promoter. Disease-causing mutations have been mapped to our structure, and their predicted effects have been tested by a set of biochemical/ functional studies. These findings together with earlier findings with a homologous protein HNF1α, help us to understand the structural basis of promoter recognition by these atypical POU transcription factors and the site-specific functional disruption by disease-causing mutations.HNF1β (hepatocyte nuclear factor 1β; also known as vHNF1 or TCF2) is a widely distributed transcription factor that plays a critical role in early vertebrate development and embryonic survival (1-3). First identified as a key regulator in the liver, HNF1β is also expressed in the pancreas, kidney, lung, ovary, testis, and throughout the gastrointestinal tract. In pancreatic β-cells, HNF1β is known to form an integrated regulatory network with other transcription factors such as HNF1α, HNF4α, Pdx-1, Foxa2, and NeuroD1 for organ development and proper function (1,4). Thus, in humans, heterozygous mutations in the HNF1β gene have been linked to neonatal diabetes (5) and the autosomal dominant subtype of diabetes known as MODY (maturity-onset diabetes of the young) (6). Extrapancreatic diseases are also increasingly recognized in different organs, especially in the kidney, with a variety of renal developmental disorders such as renal cysts, familial hypoplastic glomerulocystic kidney disease, renal malformation, and atypical familial hyperuricaemic nephropathy (7-11).POU transcription factors, which include Pit-1, Oct-1, and Unc-86 as founding members and are now expanded to more than 13 members in humans, are developmental regulators of various neuroendocrine organs, and their sequence-specific DNA binding is mediated by a bipartite motif that consists of a POU homeodomain (POU H ) and POU-specific domain (POU S ) (12,13). POU H is a 60 amino acid classic homeodomain made of three α-helices with the third as a DNA recognition helix, while POU S is an additional ∼75 amino acid all-α-helical motif that cooperates with POU H to enhance the binding affinity and specificity of DNA binding ( Figures 1 and 2) (12,14). HNF1α (MODY3 gene product, the most commonly mutated MODY protein) and HNF1β (MODY5 gene product) are atypical members of the POU transcription factors. Their POU S domains have at least one additional α-helix at the N-terminus, and the second † This work was funded by the Juvenile Diabetes Research Foundation (1-2004-506) (8,24). Recently, HNF1β has also been associated wi...

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HNF1 β/TCF2 mutations impair transactivation potential through altered co-regulator recruitment

Cited by 92 publications

References 36 publications

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

Lack of TCF2/vHNF1 in mice leads to pancreas agenesis

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,

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HNF1 β/TCF2 mutations impair transactivation potential through altered co-regulator recruitment

Cited by 92 publications

References 36 publications

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1β and HNF-1α and the abnormality of HNF-1β mutants

Lack of TCF2/vHNF1 in mice leads to pancreas agenesis

Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β,

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Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,