超级增强子 (SE) 是基因组 DNA 的广阔区域，调节涉及细胞身份和细胞命运的基因的表达。我们最近在小鼠 Vsx2 SE 中发现了发育阶段和细胞类型特异性模块。在这里，我们表明人类 VSX2 SE 模块在报告基因检测中具有相似的发育阶段和细胞类型特异性活性。通过将一个 VSX2 SE 模块的人类序列插入一只患有小眼症的小鼠体内，眼睛的大小得到了挽救。为了了解这些 SE 模块在人类视网膜发育过程中的功能，我们删除了人类胚胎干细胞中的各个模块并生成了视网膜类器官。删除一个模块会产生小类器官，重现小眼症小鼠的小眼睛表型，而删除另一个模块会导致双极神经元发育中断。这种原型SE可作为理解具有复杂表达模式的神经源性转录因子的发育阶段和细胞类型特异性效应的模型。此外，通过阐明基因调控机制，我们可以开始研究这些机制的失调如何导致表型多样性和疾病。© 2024。由 The Company of Biologies Ltd 出版。

Super-enhancers (SEs) are expansive regions of genomic DNA that regulate the expression of genes involved in cell identity and cell fate. We recently identified developmental stage- and cell type-specific modules within the murine Vsx2 SE. Here, we show that the human VSX2 SE modules have similar developmental stage- and cell type-specific activity in reporter gene assays. By inserting the human sequence of one VSX2 SE module into a mouse with microphthalmia, eye size was rescued. To understand the function of these SE modules during human retinal development, we deleted individual modules in human embryonic stem cells and generated retinal organoids. Deleting one module results in small organoids, recapitulating the small-eyed phenotype of mice with microphthalmia, while deletion of the other module led to disruptions in bipolar neuron development. This prototypical SE serves as a model for understanding 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. Published by The Company of Biologists Ltd.