Abstract
AbstractSuper-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 factorVsx2in a developmental stage- and cell-type specific manner.Vsx2is expressed in retinal progenitor cells as well as differentiated bipolar neurons and Müller glia. Mutations inVSX2in humans and mice lead to microphthalmia due to a defect in retinal progenitor cell proliferation. Deletion of a single module within theVsx2SE 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, theVsx2SE 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 oneVsx2SE 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.Summary StatementHerein, we describe how conserved modules within a single super-enhancer can regulateVSX2gene expression across species in both mice and human retinal organoids.
Publisher
Cold Spring Harbor Laboratory