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Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons |
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| Authors: | Sophie Calderari Massimiliano Ria Christelle Gérard Tatiane C. Nogueira Olatz Villate Stephan C. Collins Helen Neil Nicolas Gervasi Christophe Hue Nicolas Suarez-Zamorano Cécilia Prado Miriam Cnop Marie-Thérèse Bihoreau Pamela J. Kaisaki Jean-Baptiste Cazier Cécile Julier Mark Lathrop Michel Werner Dominique Gauguier |
| Affiliation: | 1. Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, INSERM UMR_S1138, Cordeliers Research Centre, Paris, France;2. The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;3. ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium;4. FRE3377, Institut de Biologie et de Technologies de Saclay (iBiTec-S), Commissariat à l''Energie Atomique et aux Énergies Alternatives (CEA), Gif-sur-Yvette cedex, France;5. INSERM UMR_S839, Institut du Fer à Moulin, Paris, France;6. Centre for Computational Biology, Medical School, University of Birmingham, Birmingham, United Kingdom;g. INSERM UMR-S 958, Faculté de Médecine Paris Diderot, University Paris 7 Denis-Diderot, Paris, Sorbonne Paris Cité, France;h. McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada |
| Abstract: | The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q < 0.05; enrichment range 1.40–9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting β-cells and neurons and underline the existence of trans?nosology pathways in diabetes and its co-morbidities. |
| Keywords: | AD Alzheimer's disease BN Brown Norway ChIPseq genome-wide chromatin immunoprecipitation sequencing DAVID Database for Annotation, Visualisation and Integrated Discovery G3BS Glis3-binding sites GK Goto-Kakizaki GLIS3 GLIS family zinc finger 3 isoform GO Gene Ontology GWAS Genome-wide association studies IPA Ingenuity Pathway Analysis T2D type 2 diabetes Alzheimer's disease ChIP sequencing Diabetes mellitus Goto-Kakizaki rat Quantitative trait locus Single nucleotide polymorphism |
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