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PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dateset 1]

ABSTRACT: PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dateset 1]

PROVIDER: PRJNA835054 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19082529_1.fastq.gz	Fastqsanger.gz
	SRR19082529_2.fastq.gz	Fastqsanger.gz
	SRR19082530_1.fastq.gz	Fastqsanger.gz
	SRR19082530_2.fastq.gz	Fastqsanger.gz
	SRR19082531_1.fastq.gz	Fastqsanger.gz

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PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dataset 2]

Project description:Diabetes is a major chronic disease with an excessive healthcare burden on society. A coding variant (p.Arg192His) in the transcription factor PAX4 is uniquely and reproducibly associated with altered risk for type 2 diabetes (T2D) in East Asian populations, whilst rare PAX4 alleles have been proposed to cause monogenic diabetes8. In mice, Pax4 is essential for beta cell formation but neither the role of diabetes-associated variants in PAX4 nor PAX4 itself on human beta cell development and/or function are known. Here, we demonstrate that non-diabetic carriers of either the PAX4 p.Arg192His or a newly identified p.Tyr186X allele exhibit decreased pancreatic beta cell function. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content and altered hormone gene expression. Deletion of PAX4 in isogenic human induced pluripotent stem cell (hiPSC)-derived beta-like cells resulted in de-repression of alpha cell gene expression whilst in vitro differentiation of hiPSCs from carriers of PAX4 p.192His and p.186X alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content. In silico and in vitro studies showed that these PAX4 alleles cause either reduced PAX4 expression or function. Correction of the diabetes-associated PAX4 alleles reversed these phenotypic changes. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function and its contribution to type 2 diabetes risk.

2023-08-05 | GSE203264 | GEO

PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dateset 1]

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PAX4 loss of function alters human endocrine cell development and influences diabetes risk.

Project description:PAX4 loss of function alters human endocrine cell development and influences diabetes risk.

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PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dataset 2]

Project description:PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dataset 2]

| PRJNA839336 | ENA

PAX4 loss of function alters human endocrine cell development and influences diabetes risk.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-05 | GSE203265 | GEO

Regulation of ER Homeostasis and Cell Cycle by Pax4 Enhances Î²-Cell Survival and Protects Mice Against Experimental Autoimmune Diabetes

Project description:Strategies to enhance islet b-cell survival and regeneration while refraining inflammation through manipulation of molecular targets would provide means to stably replenish the deteriorating functional b-cell mass detected in both Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM). Herein we report that over expression of the islet enriched transcription factor Pax4 refrains development of hyperglycemia in the RIP-B7.1 mouse model of T1DM through reduced insulitis, decreased b-cell apoptosis correlating with diminished DNA damage and increased proliferation. Transcriptomics revealed up regulation of genes involved in immunomodulation, cell cycle and ER homeostasis in islets over expressing Pax4 as compared to the T2DM-linked mutant variant Pax4R129W. Pax4 but not Pax4R129W protected islets from thapsigargin-mediated ER-stress apoptosis. Collectively, Pax4 is a critical signaling hub coordinating regulation of distinct molecular pathways resulting in improved b-cell fitness whereas Pax4R129W sensitizes to death under stress. More importantly we highlight potential common pharmacological targets for the treatment of DM.Â 4 groups of 3 samples each. Primary isolated islets of langerhans from either Pax4/rtTA or Pax4R121W/rtTA mice treated or not with Doxicycline.

2016-07-03 | E-GEOD-62846 | biostudies-arrayexpress

Pax4 R192H variant impairs β cell function by disrupting β cell identity and compensatory capacity in response to metabolic stress

Project description:Type 2 diabetes is characterized by progressive β cell dysfunction, yet the mechanisms by which genetic susceptibility contributes to β cell area and function remain poorly understood. Pax4 is a transcription factor critical for β cell development, and a nonsynonymous variant resulting in an arginine-to-histidine substitution at position 192 (R192H) has been associated with increased type 2 diabetes risk and identified only in individuals of East Asian ancestry. Here, we generated Pax4 R192H knock-in (Pax4R192H/R192H) mouse and integrated metabolic phenotyping, bulk and single cell transcriptomics, and human cohort analyses to investigate how Pax4 R192H mutation increases the risk of type 2 diabetes. Homozygote knock-in mice (Pax4 R192H) exhibited normal pancreatic endocrine development but developed glucose intolerance and impaired insulin secretion when fed a high-fat diet. Bulk and single-cell RNA-seq of islets from Pax4 R192H mice fed high-fat diet revealed impaired β cell adaptation to metabolic stress characterized by enhanced endoplasmic reticulum stress and impaired β cell maturity, with upregulation of dedifferentiation and α cell markers and downregulation of β cell identity genes. Pax4 deletion in β cells resulted in similar phenotypic and transcriptomic profiles to Pax4 R192H mice. In humans, the trajectories of β cell function were evaluated over a 14-year period using biennial oral glucose tolerance tests from 4,242 participants, where Pax4 R192H carriers showed 1.4-fold accelerated decline in disposition index, with increasing body mass index further exacerbating their type 2 diabetes risk. Overall, Pax4 is essential for maintaining β cell identity and compensatory function under metabolic stress, and the R192H variant predisposes to type 2 diabetes by impairing this adaptive capacity.

2026-05-11 | GSE330587 | GEO

Regulation of ER Homeostasis and Cell Cycle by Pax4 Enhances β-Cell Survival and Protects Mice Against Experimental Autoimmune Diabetes

2016-01-01 | GSE62846 | GEO

Pax4 R192H variant impairs β cell function by disrupting β cell identity and compensatory capacity in response to metabolic stress [scRNA-Seq]

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