Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Akerman, İldem; Maestro, Miguel A.; Franco, Elisa De; Grau, Vanessa; Flanagan, Sarah E.; García-Hurtado, Javier; Mittler, Gerhard; Ravassard, Philippe; Piemonti, Lorenzo; Ellard, Sian; Hattersley, Andrew T.; Ferrer, Jorge

doi:10.1016/j.celrep.2021.108981

Cited by 10 publications

(11 citation statements)

References 75 publications

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“…Glis3 also directly regulates Ins2 expression, which is significantly down across all Glis3 knockout models [ 23 , 24 , 25 , 70 ]. This correlates well with what is seen in humans (discussed in the next section), where GLIS3 appears to be a critical regulator of INS expression [ 74 ].…”

Section: Links Between Glis3 and β-Cell Maturationsupporting

confidence: 86%

“…Additionally, GLIS3 protein seems to coordinate this function with other transcription factors via co-binding of genomic loci, as has been reported for ISL1 and LDB1 [ 70 , 90 ]. Similar results have been observed in human islets, with GLIS3 binding to the human INS promoter region together with other transcription factors [ 74 ]. Not only does GLIS3 appear to bind and activate the INS promoter, but it appears to be required for binding of PDX1 and NEUROD1 to the INS promoter as well [ 74 ].…”

Section: Glis3 In Human β-Cell Developmentsupporting

confidence: 85%

“…Similar results have been observed in human islets, with GLIS3 binding to the human INS promoter region together with other transcription factors [ 74 ]. Not only does GLIS3 appear to bind and activate the INS promoter, but it appears to be required for binding of PDX1 and NEUROD1 to the INS promoter as well [ 74 ]. This evidence further supports a model of β-cell transcription factor co-binding and coordination where multiple transcription factors bind to overlapping regions and are required for proper gene regulation.…”

Section: Glis3 In Human β-Cell Developmentsupporting

confidence: 85%

“…However, GLIS3 appears to play a distinct role from these factors in that, while total endocrine cell numbers are reduced, β- and γ-cell numbers are more severely affected in Glis3 knockout mice. Moreover, GLIS3 appears to be necessary for the binding of additional transcription factors to the human INS promoter [ 74 ]. And GLIS3 is one of only a few genes that have been linked through GWAS to both Type 1 and Type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

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GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

Scoville

Jetten

2021

Cells

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Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3. Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes. As a significant progress has been made in understanding some of GLIS3’s roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors. While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy.

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Section: Links Between Glis3 and β-Cell Maturationsupporting

confidence: 86%

Section: Glis3 In Human β-Cell Developmentsupporting

confidence: 85%

Section: Glis3 In Human β-Cell Developmentsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

Scoville

Jetten

2021

Cells

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“…Details of the RNA-Seq and ChIP-Seq experiments, as well as human islet donors, were previously described ( 48 , 60 – 62 ). All transcriptomic data sets used to generate Supplemental Figure 1 , A and B, are publicly available through EMBL-EBI and GEO databases and freely accessible through http://pasqualilab.upf.edu/app/isletregulome For visualization, processed RNA-Seq and ChIP-Seq (bigWig) data files were downloaded (EBI: E-MTAB-1919, E-MTAB-1294 and GEO: GSE151405) and loaded onto the local open source University of California Santa Cruz Genome Browser ( http://genome.ucsc.edu/ ; ref.…”

Section: Methodsmentioning

confidence: 99%

Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice

Nasteska¹,

Cuozzo²,

Viloria³

et al. 2021

JCI Insight

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The alpha ketoglutarate-dependent dioxygenase, prolyl-4-hydroxylase 3 (PHD3), is a Hypoxia-Inducible Factor (HIF) target that uses molecular oxygen to hydroxylate peptidyl prolyl residues. While PHD3 has been reported to influence cancer cell metabolism and liver insulin sensitivity, relatively little is known about effects of this highly conserved enzyme in insulin-secreting β-cells in vivo. Here, we show that deletion of PHD3 specifically in β-cells (βPHD3KO) is associated with impaired glucose homeostasis in mice fed high fat diet. In the early stages of dietary fat excess, βPHD3KO islets energetically rewire, leading to defects in the management of pyruvate fate and a shift from glycolysis to increased fatty acid oxidation (FAO). However, under more prolonged metabolic stress, this switch to preferential FAO in βPHD3KO islets is associated with impaired glucose-stimulated ATP/ADP rises, Ca 2+ fluxes and insulin secretion. Thus, PHD3 might be a pivotal component of the β-cell glucose metabolism machinery in mice by suppressing the use of fatty acids as a primary fuel source during the early phases of metabolic stress.

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Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers

et al. 2022

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The pancreas is a central organ for human diseases. Most alleles uncovered by genome-wide association studies of pancreatic dysfunction traits overlap with non-coding sequences of DNA. Many contain epigenetic marks of cis-regulatory elements active in pancreatic cells, suggesting that alterations in these sequences contribute to pancreatic diseases. Animal models greatly help to understand the role of non-coding alterations in disease. However, interspecies identification of equivalent cis-regulatory elements faces fundamental challenges, including lack of sequence conservation. Here we combine epigenetic assays with reporter assays in zebrafish and human pancreatic cells to identify interspecies functionally equivalent cis-regulatory elements, regardless of sequence conservation. Among other potential disease-relevant enhancers, we identify a zebrafish ptf1a distal-enhancer whose deletion causes pancreatic agenesis, a phenotype previously found to be induced by mutations in a distal-enhancer of PTF1A in humans, further supporting the causality of this condition in vivo. This approach helps to uncover interspecies functionally equivalent cis-regulatory elements and their potential role in human disease.

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Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene

Cited by 10 publications

References 75 publications

GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

Prolyl-4-hydroxylase 3 maintains β cell glucose metabolism during fatty acid excess in mice

Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers

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