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Published on: November 8, 2017
Derivation and molecular characterization of pancreatic differentiated MODY1-iPSCs
Carmel Braverman-Gross1, Neta Nudel1, Daniel Ronen1
1The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.
Abstract:
Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes mellitus presenting at childhood or adolescence, which eventually leads to pancreatic β-cells dysfunction. The underlying genetic basis of MODY disorders is haploinsufficiency, where loss-of-function mutations in a single allele cause the diabetic phenotype in heterozygous patients. MODY1 is a type of MODY disorder resulting from a mutation in the transcription factor hepatocyte nuclear factor 4 alpha (HNF4α). In order to establish a human based model to study MODY1, we generated patient-derived induced pluripotent stem cells (iPSCs). Differentiation of these pluripotent cells towards the pancreatic lineage enabled to evaluate the effects of the MODY1 mutation and its impact on endodermal and pancreatic cells. Analyzing the gene expression profiles of differentiated MODY1 cells, revealed the outcome of HNF4α haploinsufficiency on its targets. This molecular analysis suggests that the differential expression of HNF4α target genes in MODY1 is affected by the number of HNF4α binding sites, their distance from the transcription start site, and the number of other transcription factor binding sites. These features may help explain the molecular manifestations of haploinsufficiency in MODY1 disease.
Insights
Maturity onset diabetes of the young (MODY) is a genetic diabetes. Researchers used patient stem cells to model MODY1, revealing how HNF4α gene mutations impact pancreatic cells and diabetes development.
Area of Science:
- Genetics
- Endocrinology
- Stem Cell Biology
Background:
- Maturity onset diabetes of the young (MODY) is a hereditary diabetes caused by genetic defects.
- MODY1 is characterized by mutations in the hepatocyte nuclear factor 4 alpha (HNF4α) gene, leading to pancreatic beta-cell dysfunction.
- Haploinsufficiency, a loss-of-function in one gene copy, underlies MODY disorders.
Observation:
- Patient-derived induced pluripotent stem cells (iPSCs) were generated to create a human model for MODY1.
- These iPSCs were differentiated into pancreatic lineage cells to study the effects of the MODY1 mutation.
- Gene expression profiles of MODY1 cells were analyzed to understand the impact of HNF4α haploinsufficiency.
Findings:
- HNF4α haploinsufficiency in MODY1 affects the expression of its target genes in pancreatic cells.
- Differential gene expression is influenced by HNF4α binding site characteristics (number, distance from TSS) and other transcription factor interactions.
- This molecular mechanism helps explain the cellular dysfunction observed in MODY1.
Implications:
- The iPSC-derived model provides a platform for studying MODY1 pathogenesis and potential therapeutic strategies.
- Understanding the molecular basis of HNF4α haploinsufficiency can inform the diagnosis and management of MODY1 patients.
- This research sheds light on the complex regulation of gene expression in pancreatic development and diabetes.
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