PDF(Pubmed)
Abstract：
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 have profiled VSX2 genomic occupancy during mouse retinogenesis, revealing extensive retinal genetic programs associated with VSX2 during development. VSX2 binds and transactivates its enhancer in association with the transcription factor PAX6. Mice harboring deletions in the Vsx2 regulatory landscape exhibit specific abnormalities in retinal proliferation and in bipolar cell differentiation. In one of those deletions, a complete loss of bipolar cells is associated with a bias towards photoreceptor production. VSX2 occupies cis-regulatory elements nearby genes associated with photoreceptor differentiation and homeostasis in the adult mouse and human retina, including a conserved region nearby Prdm1, a factor implicated in the specification of rod photoreceptors and suppression of bipolar cell fate. VSX2 interacts with the transcription factor OTX2 and can act to suppress OTX2-dependent enhancer transactivation of the Prdm1 enhancer. Taken together, our analyses indicate that Vsx2 expression can be temporally and spatially uncoupled at the enhancer level, and they illuminate important mechanistic insights into how VSX2 is engaged with gene regulatory networks that are essential for retinal proliferation and cell fate acquisition.
摘要：
Vsx2是视网膜增殖和双极细胞分化所必需的转录因子，但其发育作用的分子机制尚不清楚。这里,我们对小鼠视网膜发生过程中的VSX2基因组占有率进行了分析，揭示了在发育过程中与VSX2相关的广泛的视网膜遗传程序。VSX2结合并反式激活其与转录因子PAX6相关的增强子。在Vsx2调节景观中带有缺失的小鼠在视网膜增殖和双极细胞分化中表现出特定的异常。在其中一个删除中，双极细胞的完全丧失与光感受器产生的偏向有关。VSX2在成年小鼠和人类视网膜中占据与光感受器分化和稳态相关的基因附近的顺式调节元件，包括Prdm1附近的保守区域，这与视杆光感受器的规格和双极细胞命运的抑制有关。VSX2与转录因子OTX2相互作用，可以抑制Prdm1增强子的OTX2依赖性增强子反式激活。一起来看,我们的分析表明，Vsx2表达可以在增强子水平上在时间和空间上解耦，他们阐明了VSX2如何参与视网膜增殖和细胞命运获取所必需的基因调控网络的重要机制见解。
