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

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

PROVIDER: PRJNA705983 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13827322_1.fastq.gz	Fastqsanger.gz
	SRR13827322_2.fastq.gz	Fastqsanger.gz
	SRR13827323_1.fastq.gz	Fastqsanger.gz
	SRR13827323_2.fastq.gz	Fastqsanger.gz
	SRR13827324_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations K

Project description:Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human ESCs and iPSCs reprogrammed from a family with HNF1B-asscociated DKMs. Mutant organoids contained enlarged malformed tubules and displayed deregulated cell turnover. This submission contains kidney tissue samples.

2024-04-29 | E-MTAB-12822 | biostudies-arrayexpress

Human pluripotent stem cell-derived kidney organoids reveal tubular epithelial pathobiology of heterozygous HNF1B-associated dysplastic kidney malformations CL

2024-04-29 | E-MTAB-12824 | biostudies-arrayexpress

Modeling HNF1B-associated monogenic diabetes using human iPSCs reveals an early stage impairment of the pancreatic developmental program.

Project description:Heterozygous mutations in HNF1B in humans result in a multisystem disorder, including pancreatic hypoplasia and diabetes mellitus. Here we used a well-controlled human induced pluripotent stem cell pancreatic differentiation model to elucidate the molecular mechanisms underlying HNF1B-associated diabetes. Our results show that lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor (FP) stage, but HNF1B haploinsufficiency allows differentiation of multipotent pancreatic progenitor cells (MPCs) and insulin-secreting β-like cells. We show that HNF1B haploinsufficiency impairs cell proliferation in FPs and MPCs. This could be attributed to impaired induction of key pancreatic developmental genes, including SOX11, ROBO2, and additional TEAD1 target genes whose function is associated with MPC self-renewal. In this work we uncover 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.

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Monogenic diabetes study

Project description:Monogenic diabetes

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Adenoviral shRNA-based knockdown of hepatic Hnf1b (Ad-shHnf1b)

Project description:Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus (T2D) and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism 1,2,3. MicroRNA (miR)-dependent posttranscriptional gene silencing has recently been recognized to control gene expression in disease development and progression including that of insulin-resistant T2D. MiRs, whose deregulation alters hepatic insulin sensitivity include miR-143, miR-181 and miR-103/107. Here we report that expression of miR-802 is increased in liver of two obese mouse models and of obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, while reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b as a target of miR-802-dependent silencing and shRNA-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signaling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in db/db mice. Thus, the present study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism via targeting Hnf1b and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.

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Visceral Endoderm differentiation mediated by Hnf1B and is required for epiblast survival

Project description:E5.0 entails an intermediate state for primitive endoderm (PE) to visceral endoderm (VE) differentiation: a process required for proper embryonic development. Hnf1b is essential for primitive to visceral endoderm differentiation from E4.5 to E5.5. To understand development at E5.0 and pinpoint the role Hnf1b in proper embryonic development, embryos were harvest at E5.0 and single cells from three WT embryos and 3 Hnf1b KO embryos were isolated, dissociated, and scRNA sequenced using smartseq2. For experiments on WT embryos, CD1 females were crossed with CD1 or homozygous E-cadherin-GFP males. Hnf1b -/+22 line was derived through IVF of oocytes of Black6 mice with EMMA strain EM:07827(B6.129P2(D2)-Hnf1btm1Sce/Orl) Sperm, that was bought from the EMMA institution in Orleans.

2024-11-19 | E-MTAB-11140 | biostudies-arrayexpress

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2023-12-31 | GSE240072 | GEO

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