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

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.

Dominant gut Prevotella copri in gastrectomised non-obese diabetic Goto–Kakizaki rats improves glucose homeostasis through enhanced FXR signalling

“…Improved glucose tolerance and increased circulating bile acids in GK rats following intestinal P. copri enrichment concur with its beneficial metabolic role. We hypothesise that naturally increased intestinal P. copri in the GK rat contributes to the complex aetiology of diabetes in this strain by counteracting the adverse effects of permanent hyperglycaemia, along with sequence variants in genes that stimulate insulin secretion [12] and downregulated expression of genes involved in heart failure [42].…”

“…The Goto-Kakizaki (GK) rat is an inbred model of spontaneous diabetes obtained by selective enrichment of naturally occurring genetic polymorphisms [10] resulting in multifaceted pathological features relevant to type 2 diabetes in the absence of obesity. Even though diabetescausing genes have been mapped to the GK genome (reviewed in [11]) [12], bariatric surgery improves glycaemic control in this strain [13][14][15] through unknown mechanisms.…”

GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors

“…A role for GLIS3 in the nervous system is further supported by studies showing that GLIS3‐deficiency leads to the development of mild mental retardation and facial dysmorphism, and the association of single nucleotide polymorphisms (SNPs) in GLIS3 with an increased risk of Parkinson's and Alzheimer's disease . A recent study found a correlation between Glis3 variants and a significant reduction in dendritic complexity and spine density, important characteristics in several neurodegenerative diseases . Overexpression of GLIS3 was reported to be associated with ependymomas, tumors arising from the ependyma of the central nervous system .…”

Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes

“…Thus GLIS3 transcription factor is implicated to regulate MANF expression in beta cells. GWAS have identified GLIS3 as a known risk gene for T1D and T2D ( Calderari et al, 2018 ). Patients with mutations in this gene show neonatal diabetes, skeletal and other defects.…”

“…Importantly, Glis3 -/- mice become severe diabetic neonatally due to reduced beta cell mass ( Watanabe et al, 2009 ). In a genome-wide chromatin immunoprecipitation sequencing screen aimed at searching for Glis3 binding sites in INS-1 cells, 199 putative genes were found to bind Glis3 ( Calderari et al, 2018 ). Interestingly, genes with Glis3 binding sites were enriched for GWAS loci associated with metabolic diseases and neuropathologies.…”