Functional analysis of Vsx2 super-enhancer reveals an autoregulatory network governing Vsx2 expression during retinogenesis [ChIP-seq_mouse]

ABSTRACT: The roles of retinal cis-regulatory landscape in controlling the expression of gene regulatory networks important for retinogenesis remain poorly understood. 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 profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal gene regulatory networks associated with Vsx2 during development. We defined an autoregulatory loop in which VSX2 binds and transactivates its own enhancer in association with the transcription factor PAX6 . The Vsx2 regulatory landscape contains elements that are required for Vsx2 expression, retinal proliferation and proper cell type differentiation. We further show that retinae in which the Vsx2 enhancer landscape has been largely deleted suffer a bias toward photoreceptor production. Genomic data indicate that VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in mouse and human retinae, including a conserved region nearby the rod-specifying factor Prdm1. We provide evidence that VSX2 associates with OTX2 and can act to suppress OTX2-dependent enhancer transactivation of Prdm1 enhancer. Taken together, our analyses illuminate important mechanistic insights on how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.

ORGANISM(S): Mus musculus

PROVIDER: GSE196103 | GEO | 2022/07/13

REPOSITORIES: GEO