Bian Fuyun, Golestaneh Kimiasadat, Davis Emily, Khan Abdullah, Daghsni Marwa, Flohr Keevon, Liu Silvia, da Silva Susana, Pennacchio Len, Aldiri Issam
Department of Ophthalmology, Discovery Institute, University of Pittsburgh School of Medicine, Pittsburgh.
Department of Pharmacology and Chemical Biology and Drug, Discovery Institute, University of Pittsburgh School of Medicine, Pittsburgh.
bioRxiv. 2025 May 21:2025.05.19.654956. doi: 10.1101/2025.05.19.654956.
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. In this study, we present integrated transcriptional, genetic, and genomic analyses to uncover the regulatory mechanisms of SOX2, a key factor in establishing neural identity in RPCs. We show that SOX2 is preferentially enriched in the RPC-specific enhancer landscape associated with essential regulators of retinogenesis. Disruption of SOX2 expression impairs retinogenesis, marked by a selective loss of enhancer activity near genes essential for RPC proliferation and lineage specification. We identified the RPC transcription factor VSX2 as a binding partner for SOX2, and together, SOX2 and VSX2 co-target a core, retina-specific chromatin repertoire characterized by enhanced TF binding and robust chromatin accessibility. This cooperative binding establishes a shared SOX2-VSX2 transcriptional code that promotes the expression of critical regulators of neurogenesis while repressing 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 identity.
视网膜神经发生是由多能视网膜祖细胞(RPC)中一个复杂的转录因子(TF)基因调控网络(GRN)的协同活动介导的。目前对于这个GRN如何从机制上引导神经潜能仍知之甚少。在本研究中,我们进行了综合的转录、遗传和基因组分析,以揭示SOX2的调控机制,SOX2是在RPC中建立神经身份的关键因子。我们发现SOX2优先富集于与视网膜发生的关键调节因子相关的RPC特异性增强子景观中。SOX2表达的破坏会损害视网膜发生,其特征是RPC增殖和谱系特化所必需的基因附近的增强子活性选择性丧失。我们确定RPC转录因子VSX2是SOX2的结合伙伴,并且SOX2和VSX2共同靶向一个核心的、视网膜特异性染色质库,其特征是增强的TF结合和强大的染色质可及性。这种协同结合建立了一个共享的SOX2-VSX2转录密码,该密码促进神经发生关键调节因子的表达,同时抑制替代谱系细胞命运的获得。我们的数据揭示了关于转录因子如何协同作用以驱动基于染色质的视网膜神经身份遗传程序的基本生物学见解。
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