In silico searching of human and mouse genome data identifies known and unknown HNF1 binding sites upstream of β-cell genes

Lockwood, Christopher R.; Bingham, Coralie; Frayling, Timothy M.

doi:10.1016/s1096-7192(02)00225-1

Cited by 14 publications

(6 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HNF1-alpha is a transcription factor that has several roles in cells including apoptosis, proliferation, differentiation and transactivation. HNF1-alpha is also involved in the modulation of maturity-onset diabetes of the young [ 30 – 31 ]. The other transcriptional regulators include NEUROG1 and PDX1, which is a transcriptional activator of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide, and glucose transporter type 2.…”

Section: Resultsmentioning

confidence: 99%

Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes

et al. 2015

View full text Add to dashboard Cite

Type 1 diabetes (T1D) and type 2 diabetes (T2D) are associated with functional beta cell loss due to ongoing inflammation. Despite shared similarities, T1D is an autoimmune disease with evidence of autoantibody production, as well as a role for exocrine pancreas involvement. Our hypothesis is that differential protein expression occurs in disease stratified pancreas tissues and regulated proteins from endocrine and exocrine tissues are potential markers of disease and potential therapeutic targets. The study objective was to identify novel proteins that distinguish the pancreas from donors with T1D from the pancreas from patients with T2D, or autoantibody positive non-diabetic donors. Detailed quantitative comprehensive proteomic analysis was applied to snap frozen human pancreatic tissue lysates from organ donors without diabetes, with T1D-associated autoantibodies in the absence of diabetes, with T1D, or with T2D. These disease-stratified human pancreas tissues contain exocrine and endocrine tissues (with dysfunctional islets) in the same microenvironment. The expression profiles of several of the proteins were further verified by western blot. We identified protein panels that are significantly and uniquely upregulated in the three disease-stratified pancreas tissues compared to non-disease control tissues. These proteins are involved in inflammation, metabolic regulation, and autoimmunity, all of which are pathways linked to, and likely involved in, T1 and T2 diabetes pathogenesis. Several new proteins were differentially upregulated in prediabetic, T1D, and T2D pancreas. The results identify proteins that could serve as novel prognostic, diagnostic, and therapeutic tools to preserve functional islet mass in Type 1 Diabetes.

show abstract

Section: Resultsmentioning

confidence: 99%

Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Among the altered motifs, HNF1, a predominant trans-acting factor of hepatic or pancreaticbeta-cells, targets many genes involved in carbohydrate metabolism 20 . The binding of the HNF1 motif could directly activate beta-cell genes and directly influence glucose-stimulated insulin secretion in pancreatic beta-cells 21,22 . Considering these findings, we speculate that the C to G base change of rs10830962 may disturb HNF1 binding, regulate beta-cell gene expression, and thus have deleterious effects on beta-cell function.…”

Section: Discussionmentioning

confidence: 99%

Association of rs10830962 polymorphism with gestational diabetes mellitus risk in a Chinese population

Xie

Chen

Zhang

et al. 2019

Sci Rep

View full text Add to dashboard Cite

To date, only three polymorphisms (rs10830962, rs7754840 and rs1470579) are included in the genome-wide association study Catalog ( www.ebi.ac.uk/gwas ). However, the available evidence is limited in pregnant Chinese women. We aimed to explore the associations of three polymorphisms (rs10830962, rs7754840 and rs1470579) with GDM risk in a Chinese population. We conducted a case-control study (964 GDM cases and 1,021 controls) to evaluate the associations of these polymorphisms with GDM risk. A logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs). After adjustment for age, prepregnancy BMI, parity, abnormal pregnancy history and family history of diabetes, the minor allele of rs10830962 (C > G) demonstrated a significant association with an increased risk of GDM (OR = 1.16, 95% CI = 1.02–1.31, P = 0.029 in the additive model). However, no significant association was observed between the other two polymorphisms and GDM. Subsequent functional annotation shows that rs10830962 is located in the regulatory elements of pancreatic islets, alters the binding affinity of motifs and regulates SNORA8 expression. Our findings demonstrate that rs10830962 is associated with an increased risk of GDM in the Chinese population. Further functional characterization is warranted to uncover the mechanism of the genotype-phenotype association.

show abstract

“…Generally, HNF1␣ can activate gene expression either through binding to a site near the transcription start site, as shown for the SLCO1B1 (protein name OATP1B1, formerly called OATP-C/OATP2), ASBT (SLC10A2), and NPT1 genes (3,18,19,35), or through binding to sites that function as enhancers and are often located within intronic sequences, as shown for the aldolase B, HNF4, and NPT1 genes (3,15,27). Using a computer approach, we screened the proximal 1,000 bp of the promoter and all intronic sequences of the human and mouse NCTP/Ntcp genes for potential HNF1␣ binding sites.…”

Section: Discussionmentioning

confidence: 99%

Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene

Jung¹,

Hagenbuch²,

Fried³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

100

View full text Add to dashboard Cite

Hepatic uptake of bile acids is mediated by the Na(+)-taurocholate cotransporting polypeptide (NTCP; SLC10A1) of the basolateral hepatocyte membrane. Several cis-acting elements in the rat Ntcp gene promoter have been characterized. However, little is known about the mechanisms that control the expression of the human or mouse NTCP/Ntcp. We, therefore, compared the transcriptional regulation of the human and mouse NTCP/Ntcp gene with that of the rat. By computer alignment, a sequence in the 5'-regulatory region that is conserved between species was identified near the transcription start site. Huh7 cells were transfected with luciferase constructs containing the conserved region from each species. The hepatocyte nuclear factors (HNF)1alpha and -4alpha and the retinoid X receptor/retinoic acid receptor dimer (RXRalpha/RARalpha) bound and transactivated the rat but not the human or mouse NTCP/Ntcp promoters. In contrast, activation by the CCAAT/enhancer binding protein-beta was specific for human and mouse NTCP/Ntcp. The only consensus motif present in all three species was HNF3beta. HNF3beta formed a specific DNA-protein complex in electrophoretic mobility shift assays and inhibited NTCP/Ntcp promoter activity in cotransfection assays. Finally, a minor repressive effect of bile acids was only found for rat Ntcp. The transcriptional repressor small heterodimer partner (SHP) did not affect NTCP/Ntcp promoter activity. We conclude that 1) the transcriptional regulation of the conserved NTCP/Ntcp 5'-regulatory region differs considerably among human, mouse, and rat; and 2) the conserved NTCP/Ntcp regulatory region is not directly regulated by SHP. Bile acids may regulate NTCP/Ntcp indirectly by modulating the capacity of nuclear factors to activate gene expression.

show abstract

In silico searching of human and mouse genome data identifies known and unknown HNF1 binding sites upstream of β-cell genes

Cited by 14 publications

References 32 publications

Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes

Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes

Association of rs10830962 polymorphism with gestational diabetes mellitus risk in a Chinese population

Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene

Contact Info

Product

Resources

About