Publications
134 results found
van Arensbergen J, Garcia-Hurtado J, Moran I, et al., 2010, Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program, GENOME RESEARCH, Vol: 20, Pages: 722-732, ISSN: 1088-9051
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- Citations: 126
Boj SF, Petrov D, Ferrer J, 2010, Epistasis of transcriptomes reveals synergism between transcriptional activators Hnf1 alpha and Hnf4 alpha, PLoS Genetics, Vol: 6, Pages: 1-11, ISSN: 1553-7390
The transcription of individual genes is determined by combinatorial interactions between DNA–binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1α and Hnf4α control pancreatic islet β-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1α and Hnf4α functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1a+/− or pancreas-specific Hnf4a mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1α on Hnf4a gene transcription. Epistasis analysis with transcriptomes of single- and double-mutant islets revealed that Hnf1α and Hnf4α regulate common targets synergistically. Hnf1α binding in Hnf4a-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1α and Hnf4α control a common islet-cell regulatory program that is defective in human monogenic diabetes.
Gjesing AP, Larsen LH, Torekov SS, et al., 2010, Family and population-based studies of variation within the Ghrelin receptor locus in relation to measures of obesity, PLoS ONE, Vol: 5, ISSN: 1932-6203
BackgroundThe growth hormone secretagogue receptor (GHSR) is mediating hunger sensation when stimulated by its natural ligand ghrelin. In the present study, we tested the hypothesis that common and rare variation in the GHSR locus are related to increased prevalence of obesity and overweight among Whites.Methodology/Principal FindingsIn a population-based study sample of 15,854 unrelated, middle-aged Danes, seven variants were genotyped to capture common variation in an 11 kbp region including GHSR. These were investigated for their individual and haplotypic association with obesity. None of these analyses revealed consistent association with measures of obesity. A -151C/T promoter mutation in the GHSR was found in two unrelated obese patients. One family presented with complete co-segregation, but the other with incomplete co-segregation. The mutation resulted in an increased transcriptional activity (p<0.02) and introduction of a specific binding for Sp-1-like nuclear extracts relative to the wild type. The -151C/T mutation was genotyped in the 15,854 Danes with a minor allele frequency of 0.01%. No association with obesity in carriers (mean BMI: 27±4 kg/m2) versus non-carriers (mean BMI: 28±5 kg/m2) (p>0.05) could be shown.Conclusions/SignificanceIn a population-based study sample of 15,854 Danes no association between GHSR genotypes and measures of obesity and overweight was found. Also, analyses of GHSR haplotypes lack consistent associations with obesity related traits. A rare functional GHSR promoter mutation variant was identified, yet there was no consistent relationship with obesity in neither family- nor population-based studies.
Gaulton KJ, Nammo T, Pasquali L, et al., 2010, A map of open chromatin in human pancreatic islets, Nature Genetics, Vol: 42, Pages: 255-U41, ISSN: 1061-4036
Tissue-specific transcriptional regulation is central to human disease1. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements2,3,4 coupled with high-throughput sequencing (FAIRE-seq). We identified ∼80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed ∼3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes5, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.
Garin I, Edghill EL, Akerman I, et al., 2010, Recessive mutations in the <i>INS</i> gene result in neonatal diabetes through reduced insulin biosynthesis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 3105-3110, ISSN: 0027-8424
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- Citations: 150
Solar M, Cardalda C, Houbracken I, et al., 2009, Pancreatic Exocrine Duct Cells Give Rise to Insulin-Producing β Cells during Embryogenesis but Not after Birth, DEVELOPMENTAL CELL, Vol: 17, Pages: 849-860, ISSN: 1534-5807
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- Citations: 363
Gauthier BR, Wiederkehr A, Baquie M, et al., 2009, PDX1 Deficiency Causes Mitochondrial Dysfunction and Defective Insulin Secretion through TFAM Suppression, CELL METABOLISM, Vol: 10, Pages: 110-118, ISSN: 1550-4131
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- Citations: 94
Servitja J-M, Pignatelli M, Angel Maestro M, et al., 2009, Hnf1α (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver, MOLECULAR AND CELLULAR BIOLOGY, Vol: 29, Pages: 2945-2959, ISSN: 0270-7306
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- Citations: 97
Boj SF, Servitja JM, Martin D, et al., 2009, Functional targets of the monogenic diabetes transcription factors HNF-1 alpha and HNF-4 alpha are highly conserved between mice and humans, Diabetes, Vol: 58, Pages: 1245-1253, ISSN: 0012-1797
OBJECTIVE The evolutionary conservation of transcriptional mechanisms has been widely exploited to understand human biology and disease. Recent findings, however, unexpectedly showed that the transcriptional regulators hepatocyte nuclear factor (HNF)-1α and -4α rarely bind to the same genes in mice and humans, leading to the proposal that tissue-specific transcriptional regulation has undergone extensive divergence in the two species. Such observations have major implications for the use of mouse models to understand HNF-1α– and HNF-4α–deficient diabetes. However, the significance of studies that assess binding without considering regulatory function is poorly understood.RESEARCH DESIGN AND METHODS We compared previously reported mouse and human HNF-1α and HNF-4α binding studies with independent binding experiments. We also integrated binding studies with mouse and human loss-of-function gene expression datasets.RESULTS First, we confirmed the existence of species-specific HNF-1α and -4α binding, yet observed incomplete detection of binding in the different datasets, causing an underestimation of binding conservation. Second, only a minor fraction of HNF-1α– and HNF-4α–bound genes were downregulated in the absence of these regulators. This subset of functional targets did not show evidence for evolutionary divergence of binding or binding sequence motifs. Finally, we observed differences between conserved and species-specific binding properties. For example, conserved binding was more frequently located near transcriptional start sites and was more likely to involve multiple binding events in the same gene.CONCLUSIONS Despite evolutionary changes in binding, essential direct transcriptional functions of HNF-1α and -4α are largely conserved between mice and humans.
Luco RF, Maestro MA, Sadoni N, et al., 2008, Targeted deficiency of the transcriptional activator Hnf1α alters subnuclear positioning of its genomic targets, PLOS GENETICS, Vol: 4, ISSN: 1553-7404
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- Citations: 14
Pearson ER, Boj SF, Steele AM, et al., 2007, Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene., PLoS Med, Vol: 4
BACKGROUND: Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS: We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS: HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin se
Pearson ER, Boj SF, Steele AM, et al., 2007, Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the <i>HNF4A</i> gene, PLOS MEDICINE, Vol: 4, Pages: 760-769, ISSN: 1549-1277
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- Citations: 284
Ferrer J, Martin M, Marc Servitja J, 2007, Putting pancreaic cell plasticity to the test, JOURNAL OF CLINICAL INVESTIGATION, Vol: 117, Pages: 859-862, ISSN: 0021-9738
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- Citations: 4
Maestro MA, Cardalcla C, Boj SF, et al., 2007, Distinct roles of HNF1β, HNF1α, and HNF4α in regulating pancreas development, β-cell function and growth, DEVELOPMENT OF THE PANCREAS AND NEONATAL DIABETES, Vol: 12, Pages: 33-45, ISSN: 1421-7082
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- Citations: 84
Luco RF, Maestro MA, del Pozo N, et al., 2006, A conditional model reveals that induction of hepatocyte nuclear factor-1α in Hnf1α-null mutant β-cells can activate silenced genes postnatally, whereas overexpression is deleterious, DIABETES, Vol: 55, Pages: 2202-2211, ISSN: 0012-1797
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- Citations: 17
Mellitzer G, Bonné S, Luco RF, et al., 2006, IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas, EMBO JOURNAL, Vol: 25, Pages: 1344-1352, ISSN: 0261-4189
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- Citations: 144
Pierreux CE, Poll AV, Kemp CR, et al., 2006, The transcription factor hepatocyte nuclear factor-6 controls the development of pancreatic ducts in the mouse, GASTROENTEROLOGY, Vol: 130, Pages: 532-541, ISSN: 0016-5085
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- Citations: 114
Servitja JM, Ferrer J, 2004, Transcriptional networks controlling pancreatic development and beta cell function, DIABETOLOGIA, Vol: 47, Pages: 597-613, ISSN: 0012-186X
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- Citations: 169
Maestro MA, Boj SF, Luco RF, et al., 2003, <i>Hnf6</i> and <i>Tcf2</i> (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas, HUMAN MOLECULAR GENETICS, Vol: 12, Pages: 3307-3314, ISSN: 0964-6906
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- Citations: 118
Párrizas M, Boj SF, Luco RF, et al., 2003, Chromatin immunoprecipitation using isolated islets of Langerhans., Methods Mol Med, Vol: 83, Pages: 61-71, ISSN: 1543-1894
Hansen SK, Párrizas M, Jensen ML, et al., 2002, Genetic evidence that HNF-1α-dependent transcriptional control of HNF-4α is essential for human pancreatic β cell function, JOURNAL OF CLINICAL INVESTIGATION, Vol: 110, Pages: 827-833, ISSN: 0021-9738
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- Citations: 88
Hansen SK, Párrizas M, Jensen ML, et al., 2002, Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function., J Clin Invest, Vol: 110, Pages: 827-833, ISSN: 0021-9738
Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1). Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha, and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.
Mitchell SMS, Vaxillaire M, Thomas H, et al., 2002, Rare variants identified in the <i>HNF-4α</i> β-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes, DIABETOLOGIA, Vol: 45, Pages: 1344-1348, ISSN: 0012-186X
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- Citations: 11
Ferrer J, 2002, A genetic switch in pancreatic β-cells -: Implications for differentiation and haploinsufficiency, DIABETES, Vol: 51, Pages: 2355-2362, ISSN: 0012-1797
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- Citations: 62
Boj SF, Párrizas M, Maestro MA, et al., 2001, A transcription factor regulatory circuit in differentiated pancreatic cells, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 98, Pages: 14481-14486, ISSN: 0027-8424
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- Citations: 195
Párrizas M, Maestro MA, Boj SF, et al., 2001, Hepatic nuclear factor 1-α directs nucleosomal hyperacetylation to its tissue-specific transcriptional targets, MOLECULAR AND CELLULAR BIOLOGY, Vol: 21, Pages: 3234-3243, ISSN: 0270-7306
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- Citations: 112
Moritz W, Leech CA, Ferrer J, et al., 2001, Regulated expression of adenosine triphosphate-sensitive potassium channel subunits in pancreatic <i>β</i>-cells, ENDOCRINOLOGY, Vol: 142, Pages: 129-138, ISSN: 0013-7227
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- Citations: 38
Falany CN, Xie XW, Wang J, et al., 2000, Molecular cloning and expression of novel sulphotransferase-like cDNAs from human and rat brain, BIOCHEMICAL JOURNAL, Vol: 346, Pages: 857-864, ISSN: 0264-6021
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- Citations: 85
Hernández-Sánchez C, Ito Y, Ferrer J, et al., 1999, Characterization of the mouse sulfonylurea receptor 1 promoter and its regulation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 274, Pages: 18261-18270, ISSN: 0021-9258
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- Citations: 34
Hansen T, Echwald SM, Hansen L, et al., 1998, Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene, DIABETES, Vol: 47, Pages: 598-605, ISSN: 0012-1797
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- Citations: 95
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