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Series GSE203264 Query DataSets for GSE203264
Status Public on Aug 05, 2023
Title PAX4 loss of function alters human endocrine cell development and influences diabetes risk [dataset 2]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Using patient-derived hiPSCs to model pancreatic beta cell development to study mechanisms underlying diabetes risks.
 
Contributor(s) Lau HH, Ghosh S, Hoon S, Tai ES, Teo AK
Citation(s) 37777536
Submission date May 18, 2022
Last update date Nov 04, 2023
Contact name Adrian Kee Keong Teo
E-mail(s) ateo@imcb.a-star.edu.sg
Organization name IMCB, A*STAR
Department Stem Cells and Diabetes Laboratory
Street address 61 Biopolis Drive, Proteos
City Singapore
State/province Singapore
ZIP/Postal code 138673
Country Singapore
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (164)
GSM6165484 D0 is070A rep1 [Day0_WT_is070_A_RHP7332]
GSM6165485 D0 is070A rep2 [Day0_WT_is070_A_RHP7333]
GSM6165486 D0 is070A rep3 [Day0_WT_is070_A_RHP7334]
This SubSeries is part of SuperSeries:
GSE203265 PAX4 loss of function alters human endocrine cell development and influences diabetes risk.
Relations
BioProject PRJNA839336
SRA SRP375855

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Supplementary file Size Download File type/resource
GSE203264_data_counts_Singapore_counts_jan_2020.gene.counts.renamed.tsv.gz 8.0 Mb (ftp)(http) TSV
GSE203264_jan_2020.gene.tpm.renamed.tsv.gz 15.5 Mb (ftp)(http) TSV
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Raw data are available in SRA
Processed data are available on Series record
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