Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss-of-function due to MODY1/HNF4A mutation abrogates liver and pancreas differentiation from MODY1-hiPSCs

ABSTRACT: Purpose: To investigate the impact of MODY1/HNF4A mutation on foregut development using differentiated control and MODY1-hiPSCs Methods: RNA-Seq was performed on foregut/hepato-pancreatic progenitors obtained on day 14 of the directed differentiation of hiPSCs from MODY1 patients (3 clones from iN904-1, 1 clone from iN904-2) and family controls (3 clones from iN904-7, 2 clones from iN904-13). Differential expression analysis, KEGG pathway and gene ontology analyses were carried out. qRT-PCR validation was also performed using SYBR Green assays. Results: RNA-Seq and transcriptional analyses revealed that numerous foregut liver- and pancreas-related genes, including HNF4A, were downregulated in MODY1-hiPSC-derived hepato-pancreatic progenitors with a fold change ≥1.5 and p value <0.05, whereas hindgut HOX genes were upregulated. Altered expression of a number of genes were further confirmed with qRT-PCR. Conclusions: The HNF4A loss-of-function mutation (p.Ile271fs) resulted in significantly reduced HNF4A expression or HNF4A haploinsufficiency, affecting the proper development of the foregut and its derivatives. This deficiency is propagated to both hepatic and pancreatic cell fates, and may account for β cell developmental defects and the progressive deterioration of β cell function in MODY1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106335 | GEO | 2019/06/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Single-cell RNA-seq Analysis of Pancreatic and Hepatic Progenitor Cells from Tg(Prox1-EGFP) Transgenic Mouse Embryos

Project description:Formation of the hepato-pancreato-biliary organ system in mammals is a paradigm for organogenesis, whereby a small progenitor population of the ventral foregut gives rise to a multitude of different adult tissues, including liver, pancreas, gallbladder, and extra-hepatic bile ducts. The multipotent ventral foregut cell population undergoes an initial fate segregation into hepatic and pancreato-biliary progenitors in response to signaling cues from surrounding mesodermal tissues. Subsequently, pancreato-biliary progenitors give rise to ventral pancreatic and gallbladder progenitors. In this study, we used single-cell RNA sequencing to molecularly characterize progenitor populations in the ventral foregut that contribute to the formation of hepatic, pancreatic, and biliary organ rudiments throughout organogenesis.

2021-07-13 | GSE144103 | GEO

Decreased GLUT2 expression and defective glucose uptake in MODY3 human iPSC-Derived beta cells

Project description:Purpose: To investigate the impact of HNF1A mutation on the development of pancreatic endocrine progenitors using differentiated control and MODY3-hiPSCs Methods: ChIP-Seq was performed on pancreatic endocrine progenitors obtained on day 20 of the directed differentiation of control hPSCs (1 clone from H9 and 3 clones from iAgB-hiPSC) and hiPSCs from MODY3 patients (3 clones from P2. Peak calling analyses were carried out. qRT-PCR validation was also performed using SYBR Green assays. Results: ChIP-Seq analysis revealed that numerous HNF1A target genes were downregulated in MODY3-hiPSC-derived pancreatic endocrine progenitors. Altered expression of a number of genes were further confirmed with qRT-PCR. Conclusions: The H126D mutation in HNF1A does not affect the expression levels of HNF1A. However, this mutation affects the DNA binding capability of the transcription factor, thereby resulting in deficiency in the gene expression of proteins that are essential to maintain normal human beta-cell function for insulin secretion.

2021-03-22 | GSE139832 | GEO

A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs versus humans

Project description:A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner’s Glands (BGs) in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adults. These stem/progenitors in vivo in pigs are in highest numbers in BGs and in PDGS nearest the duodenum, and in humans are in BGs and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors.

2023-08-02 | GSE229270 | GEO

Transcription Factor Binding Analysis of Wild Type and HHEX-/- ES-derived Pancreatic Progentiors

Project description:The pancreas and liver arise from a common pool of progenitors in the foregut endoderm; however, the underlying molecular mechanisms driving this lineage diversification are not fully understood. We combined human pluripotent stem cell guided differentiation and sequential CRISPR-Cas9 loss-of-function screening to uncover regulators of pancreatic specification. Here we report the discovery of a cell-intrinsic requirement for HHEX, a transcription factor (TF) associated with diabetes susceptibility. HHEX promotes pancreatic differentiation through cooperation with pancreatic TFs as well as common TFs like FOXA2 that are shared by both pancreas and liver differentiation programs. Furthermore, HHEX restricts differentiation plasticity, and deletion of HHEX shifts FOXA2 interaction towards cooperation with HNF4A, driving liver differentiation. Therefore, HHEX safeguards pancreatic differentiation by promoting lineage specification while simultaneously restricting cell fate plasticity, demonstrating how organ domain demarcation requires fine tuning of TF cooperation.

2022-04-29 | GSE181478 | GEO

Chromatin Landscape Analysis of Wild Type and HHEX-/- ES-derived Pancreatic Progentiors

2022-04-29 | GSE181412 | GEO

Genomic integration of Wnt/b-catenin and BMP/Smad1 coordinates the transcriptional program of foregut and hindgut progenitors [RNA-seq]

Project description:Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how they are integrated in the genome is poorly understood. Here we identified the Xenopus foregut and hindgut progenitor transcriptomes, which are largely conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/b-catenin acts as a genome-wide toggle between foregut and hindgut programs. In addition to b-catenin-Tcf promoting hindgut gene transcription, we unexpectedly observed Wnt-repressed foregut genes associated with b-catenin-binding to DNA lacking Tcf motifs, suggesting a novel direct repression. We define how BMP and Wnt signaling are integrated in the genome with Smad1 and β-catenin co-occupying DNA elements associated with hundreds of key regulatory genes. These results extend our understanding of GI organogenesis and how Wnt and BMP may coordinate genomic responses in other contexts.

2017-02-28 | GSE87653 | GEO

Genomic integration of Wnt/b-catenin and BMP/Smad1 coordinates the transcriptional program of foregut and hindgut progenitors [ChIP-seq]

2017-02-28 | GSE87652 | GEO

Transcription Landscape Analysis of Wild Type and HHEX-/- ES-derived Pancreatic Progentiors

Project description:The pancreas and liver arise from a common pool of progenitors in the foregut endoderm; however, the underlying molecular mechanisms driving this lineage diversification are not fully understood. We combined human pluripotent stem cell guided differentiation and sequential CRISPR-Cas9 loss-of-function screening to uncover regulators of pancreatic specification. Here we report the discovery an unexpected, cell-intrinsic requirement for HHEX, a transcription factor (TF) associated with diabetes susceptibility. HHEX promotes pancreatic differentiation through cooperation with pancreatic TFs as well as common TFs like FOXA2 that are shared by both pancreas and liver differentiation programs. Furthermore, HHEX restricts differentiation plasticity, and deletion of HHEX causes a shift of FOXA2 interaction towards cooperation with HNF4A to drive liver differentiation. Our findings demonstrate a critical role for the fine tuning of TF cooperation in organ domain demarcation, as exemplified by how HHEX safeguards pancreatic differentiation by simultaneously promoting lineage specification and restricting cell fate plasticity.

2022-04-29 | GSE180521 | GEO

Dynamic regulation of chromatin accessibility and transcription factors underlies distinct organ identity and function

Project description:After gut tube closure, different regional domains develop into uniquely functional organs. Our single cell analysis demonstrates that chromatin accessibility predicts lineage fate decisions, reflecting the transcriptional profiles of individual cells. Combining with bulk analyses, we have generated a comprehensive map of epigenetic changes over developmental time, revealing how chromatin accessibility and transcription factor (TF) binding cooperate to control organ identity and differentiation. Loss of the foregut and hindgut lineage-specific TFs, Sox2 and Cdx2, leads to the acquisition of accessibility profiles similar to neighbouring organs, while Sox2 overexpression in early development induces a loss of intestinal identity and pancreatic transformation into foregut fate precursors. Moreover, ectopic expression of Sox2 in normal adult and cancer intestinal and pancreatic tissues leads to lineage alterations, demonstrating its critical role in homeostasis and cancer. Together, these studies define the chromatin and transcriptional mechanisms of organ identity and lineage plasticity in development and disease.

2022-03-27 | GSE168373 | GEO

Organ-specific gene expression in single differentiating Drosophila embryos

Project description:Age-matched stage 13 embryos were dissected and cDNA of 8 organs from each embryo were sequenced. The organs were foregut, anterior midgut, posterior midgut, hindgut, Malpighian tubules, left salivary gland, right salivary gland, ventral nerve cord. Gene expression, transcription start and stop sites, and strands of termini were analysed. SMART amplification adapters were used for finding transcript termini and for phasing.

2017-02-01 | GSE77429 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data