ArticlePLoS genetics2010
Epistasis of transcriptomes reveals synergism between transcriptional activators Hnf1alpha and Hnf4alpha.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 60 citations in OpenAlex.
- Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications.World journal of hepatology · 2025Review
- HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes.Cell metabolism · 2025Article
- Modeling combinatorial regulation from single-cell multi-omics provides regulatory units underpinning cell type landscape using cRegulon.Genome biology · 2025Article
- MODY PDX1Frontiers in endocrinology · 2025Article
- Patterns of Fitness and Gene Expression Epistasis Generated by Beneficial Mutations in the rho and rpoB Genes of Escherichia coli during High-Temperature Adaptation.Molecular biology and evolution · 2024Article
- HNF4A and HNF1A exhibit tissue specific target gene regulation in pancreatic beta cells and hepatocytes.Nature communications · 2024Article
- Molecular mechanism of HNF-1A-mediated HNF4A gene regulation and promoter-driven HNF4A-MODY diabetes.JCI insight · 2024Article
- Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells.Cell metabolism · 2023Article
- Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles.Nature communications · 2023Article
- HNF1α upregulation and promoter hypermethylation as a cause of glucose dysregulation: a case-control study of Kashmiri MODY population.Journal of endocrinological investigation · 2023Article
- Genome Editing and Human Pluripotent Stem Cell Technologies for in vitro Monogenic Diabetes Modeling.Diabetes, metabolic syndrome and obesity : targets and therapy · 2022Review
- Review
- Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells.Nature communications · 2021Article
- Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model.Disease models & mechanisms · 2021Article
- Bioinformatic Analyses of miRNA-mRNA Signature during hiPSC Differentiation towards Insulin-Producing Cells upon HNF4α Mutation.Biomedicines · 2020Article
- Identification ofProceedings of the National Academy of Sciences of the United States of America · 2019Article
- HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells.iScience · 2019Article
- CTCF maintains regulatory homeostasis of cancer pathways.Genome biology · 2018Article
- Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.Cell metabolism · 2017Article
- A suppressor locus for MODY3-diabetes.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The transcription of individual genes is determined by combinatorial interactions between DNA-binding transcription factors. The current challenge is to understand how such combinatorial interactions regulate broad genetic programs that underlie cellular functions and disease. The transcription factors Hnf1alpha and Hnf4alpha control pancreatic islet beta-cell function and growth, and mutations in their genes cause closely related forms of diabetes. We have now exploited genetic epistasis to examine how Hnf1alpha and Hnf4alpha functionally interact in pancreatic islets. Expression profiling in islets from either Hnf1a(+/-) or pancreas-specific Hnf4a mutant mice showed that the two transcription factors regulate a strikingly similar set of genes. We integrated expression and genomic binding studies and show that the shared transcriptional phenotype of these two mutant models is linked to common direct targets, rather than to known effects of Hnf1alpha on Hnf4a gene transcription. Epistasis analysis with transcriptomes of single- and double-mutant islets revealed that Hnf1alpha and Hnf4alpha regulate common targets synergistically. Hnf1alpha binding in Hnf4a-deficient islets was decreased in selected targets, but remained unaltered in others, thus suggesting that the mechanisms for synergistic regulation are gene-specific. These findings provide an in vivo strategy to study combinatorial gene regulation and reveal how Hnf1alpha and Hnf4alpha control a common islet-cell regulatory program that is defective in human monogenic diabetes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.