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A noncoding variant confers pancreatic differentiation defect

GSE249854 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2024/10/20 Platform GPL29480
Summary
GWAS provided many β cell function-associated single nucleotide polymorphisms (SNPs) without clearly pathogenic mechanism. Stepwise differentiation of pancreatic β cells provide the promise to study developmental genetic disorders. Here, we focused on SNP rs6048205 (A/G) located in downstream noncoding region of FOXA2, which was annotated with fast glucose and β cell function risk. We introduced the mutation into human pluripotent stem cells, directed pancreatic differentiation revealed that risk G mutation reduce the percentage of PDX1+NKX6-1+ progenitor cells at pancreatic progenitor 2 stage (PP2), and then defect the function of β cells in-vitro. Mechanistically, risk allele G variant could alter the upstream factor RXRA binding to ectopically promote the expression of FOXA2, which is an important transcription factor in pancreatic development.
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Direct links to NCBI, no account and no request form: the whole study as GSE249854_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 8 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1051034 and SRA study SRP477282. Searching any of these in the dataset finder brings you back here.

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