Expression data from E14.5 Onecut1 WT and KO animals
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE57917 | GEO | 2014/11/11
SECONDARY ACCESSION(S): PRJNA248446
REPOSITORIES: GEO
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Project description:In this study, we examine the consequences of the loss of two related factors, Onecut1 and Onecut2, during mouse retinal development and maturation.
2014-11-11 | GSE57918 | GEO
Project description:Genes involved in distinct diabetes types suggest shared disease mechanisms. We show that rare ONECUT1 coding variants cause monogenic recessive diabetes (neonatal or very early-onset, syndromic) in two unrelated patients, and monogenic dominant diabetes (early adult-onset) in heterozygous relatives of these and 13 additional unrelated cases. Patients heterozygous for rare ONECUT1 coding variants define a subgroup of T2D with early-onset diabetes and other features. In addition, common regulatory ONECUT1 variants are associated with multifactorial T2D. Directed differentiation of human pluripotent stem cells to the pancreatic lineage revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. We uncovered that ONECUT1 activates the pro-endocrine genes NKX6.1 and NKX2.2 through binding to their cis-regulatory elements. Globally, ONECUT1-directed gene transcription occurs in association with major islet transcription factors, at clusters of pancreas- and endocrine-specific enhancers within open chromatin. ONECUT1 regulates a transcriptional and epigenetic machinery critical for proper endocrine pancreatic development, involved in a spectrum of diabetes, monogenic recessive and dominant, and multifactorial.
2021-11-03 | PXD018887 | Pride
Project description:Hemophilia B, or the 'Royal Disease', arises from mutations in the Coagulation Factor IX (F9) gene. Mutations within the F9 promoter are associated with a remarkable form of the disease, termed Hemophilia B Leyden, in which symptoms ameliorate after puberty. Mutations at the -5/-6 site account for the majority of Leyden cases, and have been postulated to disrupt the binding of a transcriptional activator, the identity of which has remained elusive for more than twenty years. Here we show that the ONECUT transcription factors (ONECUT1/HNF6 and ONECUT2/HNF6B) bind to the -5/-6 site. The various Hemophilia B Leyden mutations that have been reported in this site inhibit ONECUT binding to varying degrees that correlate well with their associated clinical severities. In addition, expression of F9 is crucially dependent on ONECUT factors in vivo and as such, mice that are deficient in either ONECUT1, ONECUT2 or both, exhibit depleted levels of F9. Taken together, our findings establish the ONECUT transcription factors as the missing regulators of Hemophilia B Leyden that operate through the -5/-6 site.
2013-03-06 | E-MTAB-890 | biostudies-arrayexpress
Project description:The aim of this project is to locate the precise binding of the ONECUT1 transcription factor. NOTE: This study was updated on 7th May 2014. All samples, experiments, runs and files were replaced. This was due to an incorrect reagent being used in the earlier version.
2014-05-10 | E-MTAB-2060 | biostudies-arrayexpress
Project description:Background: The vertebrate retina consists of six major classes of neuronal cells. During development, these cells are generated from a pool of multipotent retinal progenitor cells (RPCs) that express the gene Vsx2. Fate-restricted RPCs have recently been identified, with limited mitotic potential and cell fate possibilities compared to multipotent RPCs. One population of fate-restricted RPCs, marked by activity of the regulatory element ThrbCRM1, gives rise to both cone photoreceptors and horizontal cells. These cells do not express Vsx2, but co-express the transcription factors (TFs) Onecut1 and Otx2, which bind to ThrbCRM1. The components of the gene regulatory networks that control the transition from multipotent to fate-restricted gene expression are not known. This work aims to identify and evaluate cis-regulatory elements proximal to Onecut1 to identify the gene regulatory networks involved in RPC fate-restriction. Method: We identified regulatory elements through ATAC-seq and conservation, followed by reporter assays to screen for activity based on temporal and spatial criteria. The regulatory elements of interest were subject to deletion and mutation analysis to identify functional sequences and evaluated by quantitative flow cytometry assays. Finally, we combined the enhancer::reporter assays with candidate TF overexpression to evaluate the relationship between the TFs, the enhancers, and early vertebrate retinal development. Statistical tests included ANOVA, Kruskal-Wallis, or unpaired t-tests.Results: Two regulatory elements, ECR9 and ECR65, were identified to be active in ThrbCRM1(+) restricted RPCs. Candidate bHLH binding sites were identified as critical sequences in both elements. Overexpression of candidate bHLH TFs revealed specific enhancer-bHLH interactions. Nhlh1 overexpression expanded ECR65 activity into the Vsx2(+) RPC population, and overexpression of NeuroD1/NeuroG2/NeuroD4 had a similar effect on ECR9. Furthermore, bHLHs that were able to activate ectopic ECR9 reporter were able to induce endogenous Otx2 expression. Conclusions: This work reports a large-scale screen to identify spatiotemporally specific regulatory elements near the Onecut1 locus. These elements were used to identify distinct populations in the developing retina. In addition, fate-restricted regulatory elements responded differentially to bHLH factors, and suggest a role for retinal bHLHs upstream of the Otx2 and Onecut1 genes during the formation of restricted RPCs from multipotent RPCs.
2020-04-17 | GSE141019 | GEO
Project description:In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic and functional studies we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations.
2024-10-19 | GSE275369 | GEO
Project description:In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic and functional studies we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations.
2024-10-19 | GSE275368 | GEO
Project description:Cis-regulatory analysis of Onecut1 in fate-restricted retinal progenitor cells
| PRJNA591782 | ENA
Project description:Mapping ONECUT1 TF binding with ChIP-exo
| PRJEB4933 | ENA
Project description:Pancreatic differentiation and specification of lineages is a tightly controlled process involving a interconnected network of transcriptional regulation. Although more knowledge on human pancreatic development is accumulating, the precise role of many transcription factors is only described in mouse. Therefore, it is of great interest to expand our knowledge using alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells. Here, we provide stage-specific data from RNA-, ChIP-, and ATAC-sequencing to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreas differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreas transcription factors and determine ONECUT1 as a crucial regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification.Our approach of dissecting the transcriptional and regulatory mechanisms revealed an important role for the specific key player ONECUT1 and will help to better understand human development and disease.
2021-10-27 | GSE167602 | GEO