Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development
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ABSTRACT:
PROVIDER: PRJNA1119636 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29270979.fastq.gz | Fastqsanger.gz | |||
| SRR29270980.fastq.gz | Fastqsanger.gz | |||
| SRR29270981.fastq.gz | Fastqsanger.gz | |||
| SRR29270982.fastq.gz | Fastqsanger.gz | |||
| SRR29270983.fastq.gz | Fastqsanger.gz |
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Project description:Identification of Evolutionarily Conserved VSX2 Enhancers in Retinal Development [RNA-seq]
| PRJNA1122781 | ENA
Project description:Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of transcription factor Vsx2 in a developmental stage- and cell-type specific manner. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.
2024-06-04 | GSE268990 | GEO
Project description:Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of transcription factor Vsx2 in a developmental stage- and cell-type specific manner. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.
2025-07-31 | GSE269620 | GEO
Project description:Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. Recently, we found that distinct modules within a murine SE regulate gene expression of master regulatory transcription factor Vsx2 in a developmental stage- and cell-type specific manner. Vsx2 is expressed in retinal progenitor cells as well as differentiated bipolar neurons and Müller glia. Mutations in VSX2 in humans and mice lead to microphthalmia due to a defect in retinal progenitor cell proliferation. Deletion of a single module within the Vsx2 SE leads to microphthalmia. Deletion of a separate module within the SE leads to a complete loss of bipolar neurons, yet the remainder of the retina develops normally. Furthermore, the Vsx2 SE is evolutionarily conserved in vertebrates, suggesting that these modules are important for retinal development across species. In the present study, we examine the ability of these modules to drive retinal development between species. By inserting the human build of one Vsx2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the implications of these SE modules in a model of human development, we generated human retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module leads to a complete loss of ON cone bipolar neurons. This prototypical SE serves as a model for uncoupling developmental stage- and cell-type specific effects of neurogenic transcription factors with complex expression patterns. Moreover, by elucidating the gene regulatory mechanisms, we can begin to examine how dysregulation of these mechanisms contributes to phenotypic diversity and disease.
| S-EPMC10614883 | biostudies-literature
Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
2022-07-13 | GSE196104 | GEO
Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
2022-07-13 | GSE196103 | GEO
Project description:The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. Vsx2 is a transcription factor essential for retinal proliferation and bipolar cell differentiation but the molecular mechanisms underlying its developmental roles are unclear. Here, we profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
2022-07-13 | GSE196097 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. The Vsx2 homeobox gene is expressed in the newly formed retinal domain during early eye development and mutations in the Vsx2 gene cause congenital microphthalmia. The primary disruptions in the early retina are compromised retinal identity (lineage infidelity), reduced proliferation, and delayed neurogenesis. One goal of the study was to use gene expression profiling to predict genetic interactions between Vsx2 and candidate functional interactors that contribute to the early retinal phenotype of the Vsx2-null mouse strain ocular retardation J (orJ). The orJ allele is a spontaneous, recessive allele caused by the presence of a premature stop codon in the Vsx2 homeodomain. The datasets contained within are from three independent experimental designs. One was to compare the retinal gene expression profiles from E12.5 embryos that are one of three genotypes: the orJ-homozygous mutant, the combinatorial orJ; Mitfmi heterozygous mutant, and the orJ-heterozygous mouse (control). Another analysis was to compare the gene expression profiles of E12.5 orJ-homozygous mutant retinal tissues cultured for 24 hour in the presence or absence of the RXR antagonist HX531. The other analysis was to compare the gene expression profiles of E12.5 orJ-homozygous mutant retinal tissues cultured for 24 hour in the presence or absence of the gamma-Secretase antagonist Dibenzazipine (DBZ).
2023-05-19 | GSE227056 | GEO
Project description:These datasets contain the transcriptomes from E12.5 mouse retinal tissues from embryos carrying three different combinations of the Vsx2 ocular retardation J (orJ) allele and the Mitf mi (mi) allele: orJ-heterozygous, which serves as the control, orJ-homozygous, and orJ-homozygous; mi-heterozygous. The orJ allele is a recessive loss of function and the mi allele is semi-dominant. Mitf is direct target of repression by Vsx2 in the retina and is an established causal factor in the orJ ocular phenotype of microphthalmia. The goal of this analysis was to determine if blocking Mitf function in the orJ mutant would restore retinal gene expression to wild type levels. All libraries were prepared and sequenced together, facilitating direct comparisons of the gene expression profiles across the 3 genotypes.
2023-05-19 | GSE227055 | GEO
Project description:Retinal neurogenesis is mediated by the coordinated activities of a complex gene regulatory network (GRN) of transcription factors (TFs) in multipotent retinal progenitor cells (RPCs). How this GRN mechanistically guides neural competence remains poorly understood. Here, we describe integrated transcriptional, genetic, and genomic analyses to identify the regulatory mechanisms of SOX2, a critical factor for RPC neural competency. We show that SOX2 is preferentially enriched in the RPC-specific enhancer landscape associated with essential regulators of retinogenesis. Perturbation of SOX2 expression leads to a failure in retinogenesis initiation as a result of selective loss of enhancer activity near key genes underlying proliferation and lineage specification. We identified the RPC transcription factor VSX2 as a binding partner for SOX2, and together they target a core retina-specific chromatin repertoire characterized by enhanced TF binding and robust chromatin accessibility. We delineate a SOX2-VSX2 common transcriptional code that promotes the expression of critical regulators of neurogenesis and suppresses the acquisition of alternative lineage cell fate. Our data illuminate fundamental biological insights on how transcription factors act in concert to drive chromatin-based genetic programs underlying retinal neural competence.
2025-06-23 | GSE281031 | GEO