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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.

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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.

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Maternal diabetes alters transcriptional programs in the developing embryo.

Project description:Exposure to maternal diabetes during pregnancy alters transcriptional profiles in the developing embryo. The enrichment, within the set of de-regulated genes, of those encoding transcriptional regulatory molecules provides support for the hypothesis that maternal diabetes affects specific developmental programs. We compared E10.5 cntrol embryos to E10.5 embryos from diabetic pregnancies in the FVB mouse strain. Diabetes was induced in 7-9 week old female FVB mice by streptozotocin. Dams whose blood glucose levels exceeded 250 mg/dl were set up for mating. Embryos were dissected at E10.5 and total RNA was isolated. Equal amounts of RNA prepared from 3 individual embryos were pooled into one sample; each embryo was from a different pregnancy. Three pools were constructed for a total of nine embryos from diabetic pregnancies, and independently three pools for control embryos.

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