GSE168071: Modelling HNF1B-associated monogenic diabetes using human iPSCs reveals an early stage impairment of the pancreatic developmental program

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Info Studies were incorporated in a barcode, matrix, feature format. This format can be found on the 10x Genomics website for processing of single cell studies to obtain the gene expression matrices. For each study, the metadata incorporated in GEO were manually curated into profiles and the samples were separated based on applicable groups and conditions. The expression data from the cells for the samples within the same profile and condition were aggregated into an expression matrix with the cell barcodes having the sample name appended to it to ensure unique cell names.

Description (from GEO)

Submission Date: Mar 02, 2021

Summary: Heterozygous mutations in HNF1B in humans result in a multi-system disorder, including pancreatic hypoplasia and diabetes mellitus. The underlying mechanisms that contribute to disease pathogenesis remain largely unknown, partially accounted by the fact that mouse models with heterozygous deletions in Hnf1b do not develop diabetes, in contrast to the phenotypes observed in MODY patients. Here we used a well-controlled human induced pluripotent stem cell pancreatic differentiation model to elucidate the molecular mechanisms underlying HNF1B-associated diabetes and pancreatic hypoplasia. Our results show that lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor stage, but HNF1B haploinsufficiency allows differentiation of multipotent pancreatic progenitor cells and insulin secreting β-like cells. We further report that HNF1B happloinsuffiency impairs cell proliferation in foregut and multipotent pancreatic progenitors (MPCs). Our analyses suggest that this could be attributed to impaired induction of key pancreatic developmental genes, including FOXA1, SOX11, ROBO2, and additional TEAD1 target genes whose function could be associated with MPCs self-renewal. Taken together, these analyses have uncovered an exhaustive list of potential HNF1B gene targets during human pancreas organogenesis whose downregulation might underlie HNF1B-associated diabetes onset in humans, thus providing an important resource to understand the pathogenesis of this disease.

GEO Accession ID: GSE168071

PMID: 34450036

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Info Preprocessing and downstream analysis were computed using the scanpy Python library and the steps of processing followed the Seurat vignette. Cells and genes with no expression or very low expression were removed from the dataset based on a predefined threshold. The data was then normalized across the expression within the cells and log normalized. The top 2000 highly variable genes were extracted to be used for downstream analysis. For each of these aggregated data matrices, the clusters were computed using the leiden algorithm. Scanpy was then used to compute the PCA, t-SNE, and UMAPs. The points in the plots are labelled by their corresponding cell type labels. The cell type labels were computed using the wilcoxon method as the differential gene expression method. The top 250 genes were then used for enrichment analysis against the CellMarker library in order to determine the most appropriate cell type label with the lowest p-value.
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