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Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells

ABSTRACT: Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells

PROVIDER: PRJNA780478 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16947500_1.fastq.gz	Fastqsanger.gz
	SRR16947500_2.fastq.gz	Fastqsanger.gz
	SRR16947501_1.fastq.gz	Fastqsanger.gz
	SRR16947501_2.fastq.gz	Fastqsanger.gz
	SRR16947502_1.fastq.gz	Fastqsanger.gz

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Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells

Project description:Studies of monogenic diabetes are particularly useful as we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes form, caused by a mutation in the HNF4A gene. Human induced pluripotent stem cells (hiPSC) provide an excellent tool for disease modelling by subsequent directed differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (3D) environment may facilitate phenotype detection. In this study, we studied MODY1 using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules we showed that the 3D context was critical to facilitate the detection of mutation-specific phenotypes. In 3D cell aggregates we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A paving the way for translational studies of new drug targets that can be used in precision diabetes medicine of MODY.

2022-04-04 | GSE188827 | GEO

Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells.

Project description:Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation in the HNF4A gene. Human-induced pluripotent stem cells (hiPSCs) provide an excellent tool for disease modeling by subsequently directing differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (three-dimensional [3D]) environment may facilitate phenotype detection. We studied MODY1 by using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules, we show that the 3D context is critical to facilitating the detection of mutation-specific phenotypes. In 3D cell aggregates, we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules, we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A, paving the way for translational studies of new drug targets that can be used in precision diabetes medicine in MODY.

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LC-MSMS study of hiPSC-derived β-like cells in different 3D Eevironments

Project description:In this project hiPSC-derived β-like cells were studied in two different 3D enviromnets; size-adjusted cell aggregates (using Aggrewell™ plates) and inside alginate capsules. The hiPSC derived from a patient with maturity-onset diabetes of the young 1 (MODY1), which is a monogenic diabetes form, caused by a mutation in the HNF4A gene. We also generated and included a CRISPR/cas9 corrected isogenic control line. Human islets were also included as positive control. In the data analysis we compared to proteome of the cells in 3D environments compared to the frat 2D enviromnet. We found HNF4A mutation specific effects with both distinct 3D environments, where the cells are challenged differentially in term of oxygen, nutrient supply and cell-to-cell contact. We identified HNF4A mutation-specific phenotypes, including a unique proteome signature suggesting metabolic changes in the alginate bead environment, and mutation-specific cellular phenotypes and a unique proteome signature in the aggregation environment.

2022-05-20 | PXD025054 | Pride

HNF4A

Project description:HNF4A

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Hnf4a regulated transcriptome

Project description:Hnf4a regulated transcriptome

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Effect of loss of HNF4A in liver and effect of ectopic expression of HNF4A in mouse fibroblast cells

Project description:To understand how HNF4A loss affects gene expression in mouse liver. We used control and HNF4A KO mouse livers for RNA sequencing. In addition, we also examined the effect of HNF4A gain in mouse fibroblast cells by ectropically expressing HNF4A in NIH3T3 cell to identify genes that are regulated by HNF4A.

2024-01-15 | GSE210842 | GEO

Loss-of-function due to MODY1/HNF4A mutation abrogates liver and pancreas differentiation from MODY1-hiPSCs

Project description:Purpose: To investigate the impact of MODY1/HNF4A mutation on foregut development using differentiated control and MODY1-hiPSCs Methods: RNA-Seq was performed on foregut/hepato-pancreatic progenitors obtained on day 14 of the directed differentiation of hiPSCs from MODY1 patients (3 clones from iN904-1, 1 clone from iN904-2) and family controls (3 clones from iN904-7, 2 clones from iN904-13). Differential expression analysis, KEGG pathway and gene ontology analyses were carried out. qRT-PCR validation was also performed using SYBR Green assays. Results: RNA-Seq and transcriptional analyses revealed that numerous foregut liver- and pancreas-related genes, including HNF4A, were downregulated in MODY1-hiPSC-derived hepato-pancreatic progenitors with a fold change ≥1.5 and p value <0.05, whereas hindgut HOX genes were upregulated. Altered expression of a number of genes were further confirmed with qRT-PCR. Conclusions: The HNF4A loss-of-function mutation (p.Ile271fs) resulted in significantly reduced HNF4A expression or HNF4A haploinsufficiency, affecting the proper development of the foregut and its derivatives. This deficiency is propagated to both hepatic and pancreatic cell fates, and may account for β cell developmental defects and the progressive deterioration of β cell function in MODY1.

2019-06-01 | GSE106335 | GEO

Total proteome analysis of HEK293, hiPSCs and hiPSC-derived neuronal progenitor cells, neurons and cardiomyocytes

Project description:DDA and DIA total proteome analysis of HEK293, kucg_2 hiPSC, and kucg_2 hiPSC-derived differentiated cells.

2025-05-02 | PXD044928 | Pride

Comprehensive characterisation of HNF4A and HNF1A genomic targets in pancreatic beta cells and hepatic cells reveals common and tissue-specific pathways and genes

Project description:To determine the downstream regulatory network of HNF4A and HNF1A, two transcription factors that play important roles in the pancreas and liver and that are associated with diabetes, we generated a comprehensive genome-wide map of the binding targets of HNF4A and HNF1A in hiPSC-derived pancreatic and hepatic cells and relevant cell lines using ChIP-Seq and molecular validation. We report binding targets of HNF4A and HNF1A that map to both known and novel gene promoters, that are common or differentially bound across different cell types and developmental stages. Overall, the detailed characterisation of the regulatory roles of HNF4A and HNF1A in pancreatic beta cells and hepatic cells will potentially shed light on how dysregulation of these factors can contribute to altered tissue development and function, and thus pathogenesis of both monogenic diabetes and T2D.

2024-02-29 | GSE206240 | GEO

Transcriptomic profiling of Hnf4a liver knockout mice (AlbCre-Hnf4a fl/fl) vs control (Hnf4a fl/fl) mice.

Project description:Transcriptomic profiling of Hnf4a liver knockout mice (AlbCre-Hnf4a fl/fl) vs control (Hnf4a fl/fl) mice.

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