TY - JOUR
T1 - Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons
AU - Calderari, Sophie
AU - Ria, Massimiliano
AU - Gérard, Christelle
AU - Nogueira, Tatiane C.
AU - Villate, Olatz
AU - Collins, Stephan C.
AU - Neil, Helen
AU - Gervasi, Nicolas
AU - Hue, Christophe
AU - Suarez-zamorano, Nicolas
AU - Prado, Cécilia
AU - Cnop, Miriam
AU - Bihoreau, Marie-thérèse
AU - Kaisaki, Pamela J.
AU - Cazier, Jean-baptiste
AU - Julier, Cécile
AU - Lathrop, Mark
AU - Werner, Michel
AU - Eizirik, Decio L.
AU - Gauguier, Dominique
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - ChIP sequencing
KW - diabetes mellitus
KW - Goto-Kakizaki rat
KW - quantitative trait locus
KW - single nucleotide polymorphism
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85029499517&partnerID=MN8TOARS
U2 - 10.1016/j.ygeno.2017.09.001
DO - 10.1016/j.ygeno.2017.09.001
M3 - Article
SN - 0888-7543
VL - 110
SP - 98
EP - 111
JO - Genomics
JF - Genomics
IS - 2
ER -
