A SOX2-VSX2 axis modulates a core cis-regulatory circuitry to safeguard retinal neural competence [RNA-seq]

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.