title: Differential transcriptional and posttranslational transcription factor 7-like regulation among nondiabetic individuals and type 2 diabetic patients.
abstract: Human genetic studies have revealed that the T minor allele of single nucleotide polymorphism rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene is strongly associated with an increased risk of diabetes by 30%-40%. Molecular and clinical studies are of great importance for understanding how this unique variation in TCF7L2 influences type 2 diabetes (T2D) onset and progression. At the molecular level, some studies have been performed in diabetic mice and pancreatic islets from healthy human donors. Whereas TCF7L2 mRNA levels are up-regulated in islets, protein levels are down-regulated. We performed studies on TCF7L2 splicing, mRNA expression, and protein levels in immortalized human lymphocytes from nondiabetic individuals and T2D patients carrying the C/C or the at-risk T/T genotype. Our results show differential expression of TCF7L2 splice variants between nondiabetic and T2D patients carrying the at-risk genotype, as well as differences in protein levels. Therefore, we investigated the regulation of splice variants, and our results propose that splicing of exon 4 is under control of the serine-arginine-rich factor transformer 2 β (TRA2B). Finally, we studied the endoplasmic reticulum stress pathways, looking for a posttranslational explanation. We saw a shift in the activation of these pathways between nondiabetic individuals and T2D patients carrying the at-risk genotype. These results suggest that, in human immortalized lymphocytes carrying the at-risk T/T genotype, first the differential expression of TCF7L2 splice variants implies a regulation, at least for exon 4, by TRA2B and second, the differential protein levels between both T/T carriers point to a different activation of endoplasmic reticulum stress pathways.
authors: Diabetes and Obesity Research Laboratory (M.P.-J., N.N., E.F-R., R.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (M.P.-J., N.N., E.F.-R., R.G.), 08017 Barcelona, Spain; Department of Medicine (R.G.), University of Barcelona, 08036 Barcelona, Spain; and Hospital Clínic de Barcelona (R.G.), 08036 Barcelona, Spain.
authors: M
authors: M
authors: Pradas-Juni
authors: N
authors: N
authors: Nicod
authors: E
authors: E
authors: Fernández-Rebollo
authors: R
authors: R
authors: Gomis
mesh_terms: D000368:Aged; D000483:Alleles; D017398:Alternative Splicing; D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D011960:Receptors, Estrogen / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D007328:Insulin; D011960:Receptors, Estrogen; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose