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Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

ABSTRACT: Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

PROVIDER: PRJNA933164 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23381862_1.fastq.gz	Fastqsanger.gz
	SRR23381862_2.fastq.gz	Fastqsanger.gz
	SRR23381863_1.fastq.gz	Fastqsanger.gz
	SRR23381863_2.fastq.gz	Fastqsanger.gz
	SRR23381864_1.fastq.gz	Fastqsanger.gz

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Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

Project description:To study the impact of an heterozygous missense variant in GLI2 in pancreatic cell differentiation and function, we established a patient-like pluripotent stem cell model. Interestingly, engineered iPSC lines carrying the identified missense variant in the gene GLI2 showed impaired differentiation into endocrine progenitors. To further characterize putative downstream mechanisms underlying the impaired endocrine differentiation of iPSCs, we performed bulk RNA-seq at three stages of differentiation (iPSC, gut tube and endocrine progenitor stages). At early stages (iPSC and gut tube stage), the transcriptome of GLI2-CTRL and GLI2-MUT-derived cells was highly comparable, with only 48 genes significantly dysregulated at gut tube stage. By contrast, differences at the transcriptome level became evident at endocrine progenitor stage [928 genes upregulated and 1070 downregulated in mutant versus control cells].

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Heterozygous missense variant in GLI2 impairs human endocrine pancreas development.

Project description:Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we apply CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in two siblings with early-onset and insulin-dependent diabetes of unknown cause. GLI2 is a primary mediator of the Hedgehog pathway, which regulates pancreatic β-cell development in mice. However, neither mutations in GLI2 nor Hedgehog dysregulation have been reported as cause or predisposition to diabetes. We establish and study a set of isogenic iPSC lines harbouring the missense variant for their ability to differentiate into pancreatic β-like cells. Interestingly, iPSCs carrying the missense variant show altered GLI2 transcriptional activity and impaired differentiation of pancreatic progenitors into endocrine cells. RNASeq and network analyses unveil a crosstalk between Hedgehog and WNT pathways, with the dysregulation of non-canonical WNT signaling in pancreatic progenitors carrying the GLI2 missense variant. Collectively, our findings underscore an essential role for GLI2 in human endocrine development and identify a gene variant that may lead to diabetes.

| S-EPMC10954617 | biostudies-literature

Transcription profiling of cells from four developmental stages of human endocrine pancreas to define genetic pathways that regulate endocrine pancreatic development

Project description:To define genetic pathways that regulate development of the endocrine pancreas, we generated transcriptional profiles of enriched cells isolated from four biologically significant stages of endocrine pancreas development: endoderm before pancreas specification, early pancreatic progenitor cells, endocrine progenitor cells and adult islets of Langerhans. These analyses implicate new signaling pathways in endocrine pancreas development, and identified sets of known and novel genes that are temporally regulated, as well as genes that spatially define developing endocrine cells from their neighbors. The differential expression of several genes from each time point was verified by RT-PCR and in situ hybridization. Moreover, we present preliminary functional evidence suggesting that one transcription factor encoding gene (Myt1), which was identified in our screen, is expressed in endocrine progenitors and may regulate alpha, beta and delta cell development. In addition to identifying new genes that regulate endocrine cell fate, this global gene expression analysis has uncovered informative biological trends that occur during endocrine differentiation.

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