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Human Pancreatic Islets Expressing HNF1A Variant Have Defective β cell Transcriptional Regulatory Networks

ABSTRACT: Human Pancreatic Islets Expressing HNF1A Variant Have Defective β cell Transcriptional Regulatory Networks

PROVIDER: PRJNA492458 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7889448_1.fastq.gz	Fastqsanger.gz
	SRR7889448_2.fastq.gz	Fastqsanger.gz
	SRR7889449_1.fastq.gz	Fastqsanger.gz
	SRR7889449_2.fastq.gz	Fastqsanger.gz
	SRR7900160_1.fastq.gz	Fastqsanger.gz

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Human Pancreatic Islets Expressing HNF1A Variant Have Defective β cell Transcriptional Regulatory Networks

Project description:Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in hepatocyte nuclear factor 1 alpha (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

2018-09-22 | GSE120299 | GEO

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

Project description:Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

| S-EPMC6307934 | biostudies-literature

Transcription profiling of pancreatic islets from Hnf1a-deficient and wild type mice

Project description:Pancreatic islets were isolated from Hnf1a (Hepatocyte nuclear factor 1 alpha) knockout and wild-type mice and cultured ex vivo for two days in RPMI medium with 10% FBS before RNA extraction. The transcription profiles were obtained using Affymetrix GeneChip Mouse Genome 430A 2.0 arrays [Mouse430A_2].

2009-03-21 | E-MEXP-1707 | biostudies-arrayexpress

Transcription profiling of pancreatic islets from heterozygous Hnf1a-mutant and wild type mice

Project description:Pancreatic islets were isolated from Hnf1a+/- (Hepatocyte nuclear factor 1 alpha) and wild-type mice and cultured ex vivo for two days in RPMI medium with 10% FBS before RNA extraction. The transcription profiles were obtained using Affymetrix GeneChip Mouse Genome 430 2.0 arrays [Mouse430_2].

2009-03-21 | E-MEXP-1979 | biostudies-arrayexpress

Chromatin immunoprecipitation using promoter microarrays to identify genes occupied by the transcriptional regulators HNF1a, HNF4a and HNF6, together with RNA polymerase II, in human liver and pancreatic islets

Project description:Here, we use chromatin immunoprecipitation combined with promoter microarrays to identify the genes occupied by the transcriptional regulators HNF1a, HNF4a and HNF6, together with RNA polymerase II, in human liver and pancreatic islets.

2004-07-15 | E-MEXP-68 | biostudies-arrayexpress

scRNA-seq of pancreatic islets from control and Haster-pKO mice

Project description:Pancreas specific deletion of the Haster promoter region results in a variegated phenotype in pancreatic islets with overexpression or silencing of the Hnf1a gene. To determine the transcriptional consequence of the overexpression or silencing of Hnf1a is islet cells from the Haster pKO mice (Haster loxP/loxP;Pdx1-Cre), we performed scRNA-seq of pancreatic islets from control and adult female Haster pKO mice.

2022-05-01 | E-MTAB-11477 | biostudies-arrayexpress

Genomic and transcriptomic profile of HNF1A-mutated adenomas: molecular signature and potential therapeutic implications

Project description:Background: Hepatocellular adenomas (HAs) are tumors that can develop under different conditions, including in patients harboring a germline mutation in HNF1A. However, little is known about the pathogenesis of such disease. This work aims at better defining what mechanisms lie under the development of this condition. Results: 6 HAs were sampled from the liver of a 17-year-old male affected by diabetes and multiple hepatic adenomatosis harboring the heterozygous pathogenic germline variant c.815G>A, p.(Arg272His) in HNF1A which has a dominant negative effect. All HAs were molecularly characterized and four of them were shown to harbor a second somatic HNF1A variant, one had a mutation in the ARID1A gene while no additional somatic changes were found in the remaining HA and in normal parenchyma. A transcriptomic profile of the same HA samples was also performed. HNF1A biallelic mutations were associated with the up-regulation of several pathways including tricarboxylic acid cycle, the metabolism of fatty acids and mTOR signaling while angiogenesis, endothelial and vascular proliferation, cell migration/adhesion, and immune response were down-regulated. Contrariwise, in the tumor harboring the ARID1A variant, angiogenesis was up-modulated while fatty acid metabolism was down-modulated. Histological analyses confirmed the molecular data. Independently of the second mutation, energetic processes and cholesterol metabolism were up-modulated while immune response was down-modulated. Conclusions: this work provides a complete molecular signature of HNF1A-associated HAs, analyzing the association between specific HNF1A variants and the development of HA, while identifying potential new therapeutic targets for non-surgical treatment.

2024-11-22 | GSE268376 | GEO

Neurog3-Cre p300/CBP mouse islets RNA-seq

Project description:We have performed RNA-seq on mouse islets lacking all p300 (p300 KO), all CBP (CBP-null), and one copy of CBP and all p300 (triallelic). The data revealed that p300 and CBP regulate some distinct but largely overlapping genes in islets. This was further confirmed by GO term and transcription factor target analyses, which suggested that these coactivators regulate genes that function similarly and converge to Hnf1a pathway.

2017-12-11 | GSE101537 | GEO

HNF1A, UTX, H3K27me3 and H3K27ac ChIP-seq in wild-type and UTX- or HNF1A-deficient mouse pancreas

Project description:HNF1A and UTX are putative tumor suppressors in pancreatic cancer. In this study, we have combined mouse genetics, transcriptomics and genome binding studies to link HNF1A and UTX in a molecular mechanism that suppresses pancreatic cancer. In this session, we have profiled UTX, HNF1A, H3K27me3 and H3K27ac in normal and UTX- or HNF1A-deficient mouse pancreas by ChIP-seq experiments. We show that HNF1A recruits UTX to its genomic targets in pancreatic acinar cells, which results in remodeling of the chromatin landscape and activation of a broad transcriptional program of differentiated acinar cells, which in turn indirectly suppresses tumor suppressor pathways.

2019-12-20 | E-MTAB-7944 | biostudies-arrayexpress

UMI-4C in control and HASTER-deficient EndoC-betaH3 cells overexpressing HNF1A

Project description:The HASTER promoter region is a cis-regulatory element that stabilizes the transcription HNF1A. If HASTER is deleted after beta cells have been formed and HNF1A is already stably expressed, HASTER is not required to maintain HNF1A activity, and is only required to provide negative feedback on HNF1A. HNF1A binding to the HASTER promoter mediates the repression of the HNF1A gene itself. To determine whether HNF1A binding to the HASTER promoter remodels 3D chromatin interactions of the HNF1A promoter, we performed UMI-4C experiments in wild type and HASTER-promoter KO EndoC-betaH3 cells with or without doxycycline-induced HNF1A overexpression using the HNF1A promoter as viewpoint.

2022-05-01 | E-MTAB-11473 | biostudies-arrayexpress

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