Mutations in BCOR, a novel co-repressor of OTX2/CRX, cause pediatric inherited retinal degeneration. Mutations in BCOR, a novel co-repressor of OTX2/CRX, cause pediatric inherited retinal degeneration

Many transcription factors regulating the production, survival and function of photoreceptor cells in the retina have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here we show that BCL6 co-repressor (BCOR), a polycomb repressive complex I factor mutated in various cancers, negatively regulates photoreceptor gene expression. Using proteomics and promoter assays, we find that BCOR interacts with the photoreceptor transcription factors OTX2 and CRX, and reduces their ability to activate the promoters of photoreceptor-specific genes, such as Rhodopsin and Nrl. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. Finally, we identify missense variants in the human BCOR gene in six families with early-onset X-linked inherited retinal degeneration (IRD). Together, this work uncovers BCOR as a co-repressor of OTX2/CRX essential for photoreceptor cell biology and survival. Overall design: RNA-seq of BCOR knockdown in mouse retina/CUT&RUN sequencing of BCOR and Otx2/Crx during retinal development and adult stages.

目前已鉴定出多种调控视网膜感光细胞生成、存活与功能的转录因子，但学界对视网膜健康与疾病中的转录共调控因子仍知之甚少。本研究证实，BCL6共抑制因子（BCL6 co-repressor, BCOR）作为一种在多种癌症中发生突变的多梳抑制复合体I（polycomb repressive complex I）因子，可负调控感光细胞的基因表达。本研究通过蛋白质组学与启动子实验发现，BCOR可与感光细胞转录因子OTX2及CRX相互作用，并削弱二者激活视紫红质（Rhodopsin）、Nrl等感光细胞特异性基因启动子的能力。CUT&RUN测序（CUT&RUN sequencing）结果进一步显示，BCOR与CRX/OTX2在全基因组范围内的结合图谱高度一致，这与其广谱共抑制活性相符。最后，本研究在6个早发性X连锁遗传性视网膜变性（early-onset X-linked inherited retinal degeneration, IRD）家系中，鉴定出人类BCOR基因存在错义变异。综上，本研究揭示BCOR作为OTX2/CRX的共抑制因子，对感光细胞的生物学功能与存活至关重要。整体实验设计：小鼠视网膜BCOR敲低样本的RNA测序（RNA-seq）、视网膜发育及成年阶段BCOR与Otx2/Crx的CUT&RUN测序。