Frontiers in Endocrinology (Feb 2023)
A long non-coding RNA that harbors a SNP associated with type 2 diabetes regulates the expression of TGM2 gene in pancreatic beta cells
- Itziar González-Moro,
- Itziar González-Moro,
- Henar Rojas-Márquez,
- Henar Rojas-Márquez,
- Maialen Sebastian-delaCruz,
- Maialen Sebastian-delaCruz,
- Jon Mentxaka-Salgado,
- Jon Mentxaka-Salgado,
- Ane Olazagoitia-Garmendia,
- Ane Olazagoitia-Garmendia,
- Ane Olazagoitia-Garmendia,
- Luis Manuel Mendoza,
- Luis Manuel Mendoza,
- Aina Lluch,
- Aina Lluch,
- Federica Fantuzzi,
- Carmen Lambert,
- Carmen Lambert,
- Jessica Ares Blanco,
- Jessica Ares Blanco,
- Jessica Ares Blanco,
- Lorella Marselli,
- Piero Marchetti,
- Miriam Cnop,
- Miriam Cnop,
- Elías Delgado,
- Elías Delgado,
- Elías Delgado,
- Elías Delgado,
- José Manuel Fernández-Real,
- José Manuel Fernández-Real,
- José Manuel Fernández-Real,
- Francisco José Ortega,
- Francisco José Ortega,
- Ainara Castellanos-Rubio,
- Ainara Castellanos-Rubio,
- Ainara Castellanos-Rubio,
- Ainara Castellanos-Rubio,
- Izortze Santin,
- Izortze Santin,
- Izortze Santin
Affiliations
- Itziar González-Moro
- Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, Spain
- Itziar González-Moro
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Henar Rojas-Márquez
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Henar Rojas-Márquez
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
- Maialen Sebastian-delaCruz
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Maialen Sebastian-delaCruz
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
- Jon Mentxaka-Salgado
- Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, Spain
- Jon Mentxaka-Salgado
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Ane Olazagoitia-Garmendia
- Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, Spain
- Ane Olazagoitia-Garmendia
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Ane Olazagoitia-Garmendia
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
- Luis Manuel Mendoza
- Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, Spain
- Luis Manuel Mendoza
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Aina Lluch
- Institut d’Investigació Biomèdica de Girona, Girona, Spain
- Aina Lluch
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Federica Fantuzzi
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
- Carmen Lambert
- Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
- Carmen Lambert
- University of Barcelona, Barcelona, Spain
- Jessica Ares Blanco
- Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
- Jessica Ares Blanco
- Endocrinology and Nutrition Department, Central University Hospital of Asturias (HUCA), Oviedo, Spain
- Jessica Ares Blanco
- 0Department of Medicine, University of Oviedo, Oviedo, Spain
- Lorella Marselli
- 1Department of Clinical and Experimental Medicine, Cisanello University Hospital, Pisa, Italy
- Piero Marchetti
- 1Department of Clinical and Experimental Medicine, Cisanello University Hospital, Pisa, Italy
- Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
- Miriam Cnop
- 2Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
- Elías Delgado
- Health Research Institute of the Principality of Asturias (ISPA), Oviedo, Spain
- Elías Delgado
- Endocrinology and Nutrition Department, Central University Hospital of Asturias (HUCA), Oviedo, Spain
- Elías Delgado
- 0Department of Medicine, University of Oviedo, Oviedo, Spain
- Elías Delgado
- 3Spanish Biomedical Research Network in Rare Diseases (CIBERER), Madrid, Spain
- José Manuel Fernández-Real
- Institut d’Investigació Biomèdica de Girona, Girona, Spain
- José Manuel Fernández-Real
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- José Manuel Fernández-Real
- 4Department of Medical Sciences, School of Medicine, University of Girona, Oviedo, Spain
- Francisco José Ortega
- Institut d’Investigació Biomèdica de Girona, Girona, Spain
- Francisco José Ortega
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Ainara Castellanos-Rubio
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Ainara Castellanos-Rubio
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
- Ainara Castellanos-Rubio
- 5Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre, Madrid, Spain
- Ainara Castellanos-Rubio
- 6Ikerbasque - Basque Foundation for Science, Bilbao, Spain
- Izortze Santin
- Department of Biochemistry and Molecular Biology, University of the Basque Country UPV/EHU, Leioa, Spain
- Izortze Santin
- Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Izortze Santin
- 5Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre, Madrid, Spain
- DOI
- https://doi.org/10.3389/fendo.2023.1101934
- Journal volume & issue
-
Vol. 14
Abstract
IntroductionMost of the disease-associated single nucleotide polymorphisms (SNPs) lie in non- coding regions of the human genome. Many of these variants have been predicted to impact the expression and function of long non-coding RNAs (lncRNA), but the contribution of these molecules to the development of complex diseases remains to be clarified.MethodsHere, we performed a genetic association study between a SNP located in a lncRNA known as LncTGM2 and the risk of developing type 2 diabetes (T2D), and analyzed its implication in disease pathogenesis at pancreatic beta cell level. Genetic association study was performed on human samples linking the rs2076380 polymorphism with T2D and glycemic traits. The pancreatic beta cell line EndoC-bH1 was employed for functional studies based on LncTGM2 silencing and overexpression experiments. Human pancreatic islets were used for eQTL analysis.ResultsWe have identified a genetic association between LncTGM2 and T2D risk. Functional characterization of the LncTGM2 revealed its implication in the transcriptional regulation of TGM2, coding for a transglutaminase. The T2Dassociated risk allele in LncTGM2 disrupts the secondary structure of this lncRNA, affecting its stability and the expression of TGM2 in pancreatic beta cells. Diminished LncTGM2 in human beta cells impairs glucose-stimulated insulin release.ConclusionsThese findings provide novel information on the molecular mechanisms by which T2D-associated SNPs in lncRNAs may contribute to disease, paving the way for the development of new therapies based on the modulation of lncRNAs.
Keywords
- long non-coding RNA
- type 2 diabetes
- single nucleotide pholymorphism (SNP)
- pancreatic beta cell
- transglutaminase 2
