Targeting GLP-1 signaling ameliorates cystogenesis in a zebrafish model of nephronophthisis
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PROVIDER: PRJNA1235623 | ENA |
REPOSITORIES: ENA
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Project description:Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, with no effective disease-modifying therapies currently available. Here, we identify glucagon-like peptide-1 (GLP-1) signaling as a novel therapeutic target for NPH through a systematic drug repurposing screen in zebrafish. By simultaneously depleting nphp1 and nphp4, we developed a robust zebrafish model that recapitulates key features of human NPH, including glomerular cyst formation. Our screen revealed that dipeptidyl peptidase-4 (DPP4) inhibitors (Omarigliptin and Linagliptin) and GLP-1 receptor agonists (Semaglutide) significantly reduce cystogenesis in a dose-dependent manner. Genetic analysis demonstrated that GLP-1 receptor signaling is important for maintaining pronephros integrity, with gcgra and gcgrb (GLP-1 receptor genes) playing a particularly important role. Transcriptomic profiling identified adenosine receptor A2ab (adora2ab) as a key downstream effector of GLP-1 signaling, which regulates ciliary morphology and prevents cyst formation. Notably, nphp1/nphp4 double mutant zebrafish exhibited upregulation of gcgra as a compensatory mechanism, explaining their resistance to cystogenesis. This compensation was disrupted by targeted depletion of GLP-1 receptors or inhibition of adenylate cyclase, resulting in enhanced cyst formation specifically in the mutant background. Our findings establish a signaling cascade from GLP-1 receptors to adora2ab in regulating ciliary organization and preventing cystogenesis, offering new therapeutic opportunities for NPH through repurposing of FDA-approved medications with established safety profiles.
2025-08-01 | GSE291847 | GEO
Project description:Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease
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Project description:Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from Pluripotent Stem Cells (iPSCs) and inform off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that govern T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP controls the cell fate decision between myeloid and lymphoid lineages in hematopoietic stem and progenitor cells (HSPCs). Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, chemical-induced epigenetic reprogramming via G9a/GLP inhibition facilitates the generation of robust iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express Chimeric Antigen Receptors, the epigenetically engineered iPSC-T cells exhibit enhanced antitumor activity both in vitro and in a xenograft mouse model.
2024-09-30 | GSE248715 | GEO
Project description:Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from Pluripotent Stem Cells (iPSCs) and inform off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that govern T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP controls the cell fate decision between myeloid and lymphoid lineages in hematopoietic stem and progenitor cells (HSPCs). Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, chemical-induced epigenetic reprogramming via G9a/GLP inhibition facilitates the generation of robust iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express Chimeric Antigen Receptors, the epigenetically engineered iPSC-T cells exhibit enhanced antitumor activity both in vitro and in a xenograft mouse model.
2024-09-30 | GSE248714 | GEO
Project description:To determine the translational status of mRNAs in glp-4 mutant animals, we analyzed total and polysomal RNA levels by tiling arrays A total of 8 samples was analyzed (quadruplicates of glp-4_total and glp-4_polysomal, respectively)
2015-01-08 | E-GEOD-62860 | biostudies-arrayexpress
Project description:Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from Induced Pluripotent Stem Cells (iPSCs) and facilitate off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that influence T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP inhibition during specific time windows of differentiation of hematopoietic stem and progenitor cells (HSPCs) skews cell fates towards lymphoid lineages. Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, G9a/GLP inhibition facilitates the generation of robust iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express chimeric antigen receptors, the epigenetically engineered iPSC-T cells exhibit enhanced effector functions in vitro and durable antitumor activity in a xenograft mouse model.
2024-08-26 | GSE275650 | GEO
Project description:Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [ChIP-seq]
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Project description:Nrf2-mediated enhancer activation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease [RNA-seq]
| PRJNA594607 | ENA
Project description:ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by neurodevelopmental defects including Autism. Though conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 remain unclear. We identified its murine homolog ZFP462 in a screen for mediators of epigenetic gene silencing. Here, we show that ZFP462 safeguards neural lineage specification of mouse embryonic stem cells (ESCs) by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to silence mesoendodermal genes. ZFP462 binds to transposable elements (TEs) that are potential enhancers harboring ESC-specific transcription factor (TF) binding sites. Recruiting G9A/GLP, ZFP462 seeds heterochromatin, restricting TF binding. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of mesoendodermal genes. Taken together, ZFP462 confers lineage- and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of lineage non-specific genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.
2023-05-10 | PXD037238 | Pride
Project description:glp-4 L4 vs mixed stage reference Keywords: other
2003-12-31 | GSE718 | GEO