Similar Datasets
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 | GSE281032 | 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
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 | GSE281030 | GEO
Project description:A SOX2-VSX2 axis modulates a core cis-regulatory circuitry to safeguard retinal neural competence
| PRJNA1181861 | ENA
Project description:A SOX2-VSX2 axis modulates a core cis-regulatory circuitry to safeguard retinal neural competence [ATAC-seq]
| PRJNA1181862 | ENA
Project description:A SOX2-VSX2 axis modulates a core cis-regulatory circuitry to safeguard retinal neural competence [RNA-seq]
| PRJNA1181863 | ENA
Project description:A SOX2-VSX2 axis modulates a core cis-regulatory circuitry to safeguard retinal neural competence [CUT&RUN]
| PRJNA1181864 | ENA
Project description:Three dimensional (3D) culture techniques are frequently used for CNS tissue modeling and organoid production, including generation of retina-like tissues. A proposed advantage of these 3D systems is their potential to more closely approximate in vivo cellular microenvironments, which could translate into improved manufacture and/or maintenance of neuronal populations. Visual System Homeobox 2 (VSX2) labels all multipotent retinal progenitor cells (RPCs) and is known to play important roles in retinal development. In contrast, the proneural transcription factor Acheate scute-like 1 (ASCL1) is expressed transiently in a subset of RPCs, but is required for the production of most retinal neurons. Therefore, we asked whether the presence of VSX2 and ASCL1 could gauge neurogenic potential in 3D retinal cultures derived from human prenatal tissue or ES cells (hESCs). Short term prenatal 3D retinal cultures displayed multiple characteristics of human RPCs (hRPCs) found in situ, including robust expression of VSX2. Upon initiation of hRPC differentiation, there was a small increase in co-labeling of VSX2+ cells with ASCL1, along with a modest increase in the number of PKCα+ neurons. However, 3D prenatal retinal cultures lost expression of VSX2 and ASCL1 over time while concurrently becoming refractory to neuronal differentiation. Conversely, 3D optic vesicles derived from hESCs (hESC-OVs) maintained a robust VSX2+ hRPC population that could spontaneously co-express ASCL1 and generate photoreceptors and other retinal neurons for an extended period of time. These results show that VSX2 and ASCL1 can serve as markers for neurogenic potential in cultured hRPCs. Furthermore, unlike hESC-OVs, maintenance of 3D structure does not independently convey an advantage in the culture of prenatal hRPCs, further illustrating differences in the survival and differentiation requirements of hRPCs extracted from native tissue vs. those generated entirely in vitro.
| S-EPMC4546156 | biostudies-literature
Project description: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 have profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal genetic programs associated with VSX2 during development. VSX2 binds and transactivates its enhancer in association with the transcription factor PAX6. Mice harboring deletions in the Vsx2 regulatory landscape exhibit specific abnormalities in retinal proliferation and in bipolar cell differentiation. In one of those deletions, a complete loss of bipolar cells is associated with a bias towards photoreceptor production. VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in the adult mouse and human retina, including a conserved region nearby Prdm1, a factor implicated in the specification of rod photoreceptors and suppression of bipolar cell fate. VSX2 interacts with the transcription factor OTX2 and can act to suppress OTX2-dependent enhancer transactivation of the Prdm1 enhancer. Taken together, our analyses indicate that Vsx2 expression can be temporally and spatially uncoupled at the enhancer level, and they illuminate important mechanistic insights into how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
| S-EPMC9440754 | biostudies-literature
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