Significance Eukaryotic cells depend on precise genome organization within the nucleus to maintain an appropriate gene-expression profile. Critical to this process is the packaging of functional domains of open and closed chromatin to specific regions of the nucleus, but how this is regulated remains unclear. In this study, we show that the zinc finger protein Casz1 regulates higher-order nuclear organization of rod photoreceptors in the mouse retina by repressing nuclear lamina function, which leads to central localization of heterochromatin. Loss of Casz1 in rods leads to an abnormal transcriptional profile followed by degeneration. These results identify Casz1 as a regulator of higher-order genome organization.