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Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E7987-E7996. doi: 10.1073/pnas.1803069115. Epub 2018 Aug 2.

Casz1 controls higher-order nuclear organization in rod photoreceptors.

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Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada;
Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0G4, Canada.
Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Division of Experimental Medicine, McGill University, Montréal, QC H3A 0G4, Canada.
Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.


Genome organization plays a fundamental role in the gene-expression programs of numerous cell types, but determinants of higher-order genome organization are poorly understood. In the developing mouse retina, rod photoreceptors represent a good model to study this question. They undergo a process called "chromatin inversion" during differentiation, in which, as opposed to classic nuclear organization, heterochromatin becomes localized to the center of the nucleus and euchromatin is restricted to the periphery. While previous studies showed that the lamin B receptor participates in this process, the molecular mechanisms regulating lamina function during differentiation remain elusive. Here, using conditional genetics, we show that the zinc finger transcription factor Casz1 is required to establish and maintain the inverted chromatin organization of rod photoreceptors and to safeguard their gene-expression profile and long-term survival. At the mechanistic level, we show that Casz1 interacts with the polycomb repressor complex in a splice variant-specific manner and that both are required to suppress the expression of the nuclear envelope intermediate filament lamin A/C in rods. Lamin A is in turn sufficient to regulate heterochromatin organization and nuclear position. Furthermore, we show that Casz1 is sufficient to expand and centralize the heterochromatin of fibroblasts, suggesting a general role for Casz1 in nuclear organization. Together, these data support a model in which Casz1 cooperates with polycomb to control rod genome organization, in part by silencing lamin A/C.


chromatin; mouse; neurodegeneration; photoreceptors; retina

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