Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons

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, Decio L. Eizirik, Dominique Gauguier

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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.
Original languageEnglish
Pages (from-to)98-111
Number of pages14
JournalGenomics
Volume110
Issue number2
Early online date11 Sep 2017
DOIs
Publication statusPublished - 2018

Keywords

  • Alzheimer's disease
  • ChIP sequencing
  • diabetes mellitus
  • Goto-Kakizaki rat
  • quantitative trait locus
  • single nucleotide polymorphism

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