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Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE161028 | GEO | 2020/11/07

REPOSITORIES: GEO

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Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function [RNA-seq]

Project description:To investigate the relationship between key beta-cell transcription factors Hnf4a and Foxo1.

2020-11-07 | GSE161027 | GEO

Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function [ChIP-seq]

Project description:To identify transcription factors in Foxo1's network with H3K27ac ChIPseq performed in WT and beta cell-specific Foxo1 knockout beta cells.

2020-11-07 | GSE161026 | GEO

Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function.

Project description:ObjectiveGenetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components and act through β-cell-specific enhancers. However, their relationship is unclear.MethodsIn this report, we show by genome-wide interrogation of chromatin modifications that ablation of FoxO1 in mature β-cells enriches active Hnf4α enhancers according to a HOMER analysis.ResultsTo model the functional significance of this predicted unusual enhancer utilization, we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions as indicated by their responses to sulfonylurea and calcium fluxes. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues was completely reversed in double mutants lacking FoxO1 and Hnf4α. Gene expression analyses revealed distinct epistatic modalities by which the two transcription factors regulate networks associated with reversal of β-cell dysfunction. An antagonistic network regulating glycolysis, including β-cell "disallowed" genes, and a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion.ConclusionsThe findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.

| S-EPMC8225970 | biostudies-literature

Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function

Project description:Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function

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Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function [ChIP-seq]

Project description:Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function [ChIP-seq]

| PRJNA675132 | ENA

Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function [RNA-seq]

Project description:Antagonistic role of Hnf4a and FoxO1 metabolic networks through enhancer interactions in beta-cell function [RNA-seq]

| PRJNA675133 | ENA

Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation.

Project description:Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines.

| S-EPMC4612615 | biostudies-literature

Transcriptional networks driving enhancer function in the CFTR gene.

Project description:A critical cis-regulatory element for the CFTR (cystic fibrosis transmembrane conductance regulator) gene is located in intron 11, 100 kb distal to the promoter, with which it interacts. This sequence contains an intestine-selective enhancer and associates with enhancer signature proteins, such as p300, in addition to tissue-specific TFs (transcription factors). In the present study we identify critical TFs that are recruited to this element and demonstrate their importance in regulating CFTR expression. In vitro DNase I footprinting and EMSAs (electrophoretic mobility-shift assays) identified four cell-type-selective regions that bound TFs in vitro. ChIP (chromatin immunoprecipitation) identified FOXA1/A2 (forkhead box A1/A2), HNF1 (hepatocyte nuclear factor 1) and CDX2 (caudal-type homeobox 2) as in vivo trans-interacting factors. Mutation of their binding sites in the intron 11 core compromised its enhancer activity when measured by reporter gene assay. Moreover, siRNA (small interfering RNA)-mediated knockdown of CDX2 caused a significant reduction in endogenous CFTR transcription in intestinal cells, suggesting that this factor is critical for the maintenance of high levels of CFTR expression in these cells. The ChIP data also demonstrate that these TFs interact with multiple cis-regulatory elements across the CFTR locus, implicating a more global role in intestinal expression of the gene.

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Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity.

Project description:In Wnt-stimulated cells, beta-catenin becomes stabilized in the cytoplasm, enters the nucleus and interacts with HMG box transcription factors of the lymphoid-enhancing factor-1 (LEF-1)/T-cell factor (TCF) family, thereby stimulating the transcription of specific target genes. We recently identified Pontin52 as a nuclear protein interacting with beta-catenin and the TATA-box binding protein (TBP), suggesting its involvement in regulating beta-catenin-mediated transactivation. Here, we report the identification of Reptin52 as an interacting partner of Pontin52. Highly homologous to Pontin52, Reptin52 likewise binds beta-catenin and TBP. Using reporter gene assays, we show that the two proteins antagonistically influence the transactivation potential of the beta-catenin-TCF complex. Furthermore, we demonstrate the evolutionary conservation of this mechanism in Drosophila. dpontin and dreptin are essential genes that act antagonistically in the control of Wingless signalling in vivo. These results indicate that the opposite action of Pontin52 and Reptin52 on beta-catenin-mediated transactivation constitutes an additional mechanism for the control of the canonical Wingless/Wnt pathway.

| S-EPMC305835 | biostudies-literature

Mutant FOXO1 controls an oncogenic network via enhancer accessibility.

Project description:Transcriptional dysregulation is a hallmark of diffuse large B cell lymphoma (DLBCL), as transcriptional regulators are frequently mutated. However, our mechanistic understanding of how normal transcriptional programs are co-opted in DLBCL has been hindered by a lack of methodologies that provide the temporal resolution required to separate direct and indirect effects on transcriptional control. We applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated (mFOXO1) in DLBCL. The combination of rapid degradation of mFOXO1, nascent transcript detection, and assessment of chromatin accessibility allowed us to identify the direct targets of mFOXO1. mFOXO1 was required to maintain accessibility at specific enhancers associated with multiple oncogenes, and mFOXO1 degradation impaired RNA polymerase pause-release at some targets. Wild-type FOXO1 appeared to weakly regulate many of the same targets as mFOXO1 and was able to complement the degradation of mFOXO1 in the context of AKT inhibition.

| S-EPMC11019358 | biostudies-literature

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