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Profiling of chromatin accessibility in fibroblasts, iPSCs, iPSC-derived neurons and cells overexpressing Onecut transcription factors (OC1, OC2, OC3)

ABSTRACT: Remodeling of chromatin accessibility is necessary for successful reprogramming of fibroblasts to neurons. However, it is still not fully known which transcription factors can induce a neuronal chromatin accessibility profile when overexpressed in fibroblasts. To identify such transcription factors, we here used ATAC-sequencing to generate differential chromatin accessibility profiles between human fibroblasts and iNeurons, an in vitro neuronal model system obtained by overexpression of Neurog2 in induced pluripotent stem cells (iPSCs). We found that the ONECUT transcription factor sequence motif was strongly associated with differential chromatin accessibility between iNeurons and fibroblasts. All three ONECUT transcription factors associated with this motif (ONECUT1, ONECUT2 and ONECUT3) induced neuronal morphology and expression of neuronal genes within two days of overexpression in fibroblasts. We observed widespread remodeling of chromatin accessibility; in particular, we found that chromatin regions that contain the ONECUT motif were in- or lowly accessible in fibroblasts and became accessible after the overexpression of ONECUT1, ONECUT2 or ONECUT3. There was substantial overlap with iNeurons, still, many regions that gained accessibility following ONECUT overexpression were not accessible in iNeurons. Our study highlights the potential of ONECUT transcription factors for direct neuronal reprogramming.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE120083 | GEO | 2019/04/05

REPOSITORIES: GEO

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Profiling of gene expression using RNA-Seq in fibroblasts, iPSCs, iPSC-derived neurons and cells overexpressing Onecut transcription factors

Project description:Remodeling of chromatin accessibility is necessary for successful reprogramming of fibroblasts to neurons. However, it is still not fully known which transcription factors can induce a neuronal chromatin accessibility profile when overexpressed in fibroblasts. To identify such transcription factors, we here used ATAC-sequencing to generate differential chromatin accessibility profiles between human fibroblasts and iNeurons, an in vitro neuronal model system obtained by overexpression of Neurog2 in induced pluripotent stem cells (iPSCs). We found that the ONECUT transcription factor sequence motif was strongly associated with differential chromatin accessibility between iNeurons and fibroblasts. All three ONECUT transcription factors associated with this motif (ONECUT1, ONECUT2 and ONECUT3) induced neuronal morphology and expression of neuronal genes within two days of overexpression in fibroblasts. We observed widespread remodeling of chromatin accessibility; in particular, we found that chromatin regions that contain the ONECUT motif were in- or lowly accessible in fibroblasts and became accessible after the overexpression of ONECUT1, ONECUT2 or ONECUT3. There was substantial overlap with iNeurons, still, many regions that gained accessibility following ONECUT overexpression were not accessible in iNeurons. Our study highlights the potential of ONECUT transcription factors for direct neuronal reprogramming.

2019-04-05 | GSE120081 | GEO

A CpG mutational hotspot in a ONECUT (HNF6) binding site accounts for the prevalent variant of Hemophilia B Leyden

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

Expression data from E14.5 Onecut1 WT and KO animals

Project description:In this study, we examine the consequences of the loss of two related factors, Onecut1 and Onecut2, during mouse retinal development.

2014-11-11 | GSE57917 | GEO

Expression data from adult Onecut2 WT and KO animals

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

Homeostatic maintenance and age-related functional decline in the Drosophila ear

Project description:Age-related hearing loss (ARHL) is a threat to future human wellbeing. Multiple factors contributing to the terminal auditory decline have been identified; but a unified understanding of ARHL - or the homeostatic maintenance of hearing before its breakdown - is missing. We here present an in-depth analysis of homeostasis and ageing in the antennal ears of the fruit fly Drosophila melanogaster. We show that Drosophila, just like humans, display ARHL. By focusing on the phase of dynamic stability prior to the eventual hearing loss we discovered a set of evolutionarily conserved homeostasis genes. The transcription factors Onecut (closest human orthologues: ONECUT2, ONECUT3), Optix (SIX3, SIX6), Worniu (SNAI2) and Amos (ATOH1, ATOH7, ATOH8, NEUROD1) emerged as key regulators, acting upstream of core components of the fly’s molecular machinery for auditory transduction and amplification. Adult-specific manipulation of homeostatic regulators in the fly’s auditory neurons accelerated - or protected against - ARHL.

2020-04-03 | GSE148023 | GEO

Changes in chromatin accessibility and gene expression induced by overexpression of ONECUT transcription factors

Project description:Changes in chromatin accessibility and gene expression induced by overexpression of ONECUT transcription factors

| PRJNA491706 | ENA

Identifying transcriptional targets of ONECUT3 by RNAseq

Project description:We report the direct target genes of the aberrant expression of ONECUT3 through next generation sequencing. We combine RNA-seq and ChIP-seq to identify target genes of ONECUT3 overexpression. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays were performed on TP53-KO mouse embryonic fibroblast MEF with or without Doxycycline (100 ng/ml) to identify target genes both bound and regulated by ONECUT3. We found that genes related with sister chromosome exchange separation, mitotic nuclear division, and chromosome segregation were significantly upregulated by high level of ONECUT3. The top 10 directly activated target genes predicted by Binding and Expression Target Analysis (BETA) include Incenp and Cdca8, which are the critical components of Chromosomal Passenger Complex (CPC). Through this observation, we conclude that main role of ONECUT3 as transcription factors is to upregulate mRNA transcription of mitotic process. This sutdy provide new insight of genetic network of how dysfunctional ONECUT3 underlies mitotic defects and Chromosomal instability.

2024-03-01 | GSE202693 | GEO

Identifying transcriptional targets of ONECUT3 by ChIP-seq

2024-03-01 | GSE202680 | GEO

RNA-seq, ATAC-seq and DNA-methylation array data of human oligodendrocyte-like cells derived from transdifferentiated fibroblasts

Project description:One-step reprogramming of human fibroblasts into oligodendrocyte-like cells. We characterized the expression, chromatin accessibility and methylation profile of human oligodendrocyte-like cells derived using a new protocol for the direct transdifferentiation of human fibroblasts into oligodendrocyte-like cells. Direct conversion of fibroblasts was induced by ectopic overexpression of SOX10, OLIG2 and NKX6.2. The aim of the experiments was to characterise the transcriptional response and associated chromatin changes following transdifferentiation. In addition, profiles of primary human oligodendrocytes were produced.

2021-03-22 | E-MTAB-7838 | biostudies-arrayexpress

Mutations and variants of ONECUT1 in diabetes

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

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