FIZ1 is part of the regulatory protein complex on active photoreceptor-specific gene promoters in vivo.
FIZ1 is part of the regulatory protein complex on active photoreceptor-specific gene promoters in vivo.
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DOI：
10.1186/1471-2199-9-87
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发表时间：
2008-10-14
影响因子：
--
通讯作者：
Mitton KP
中科院分区：
文献类型：
--
作者：
Mali RS;Peng GH;Zhang X;Dang L;Chen S;Mitton KP
FIZ 1（Flt-3 Interacting Zinc finger）是一种广泛表达的功能未知的蛋白质。我们以前报道过，在哺乳动物视网膜中，FIZ 1与NRL（神经视网膜亮氨酸拉链）相互作用，NRL是视杆细胞感光器特异性基因的重要转录激活因子。视网膜中FIZ 1的浓度在感光体末端成熟期间增加，此时两个关键转录因子NRL和CRX（锥-杆同源异型盒）在感光体特异性基因（即视紫红质，Pde 6 b）的启动子上变得可检测。为了确定FIZ 1是否参与调节CRX介导的转录激活，我们检查了FIZ 1在小鼠神经视网膜中的亚细胞位置，其与CRX相互作用的能力，以及其与CRX/NRL靶基因的相关性。FIZ 1存在于成人光感受器以及其他视网膜神经元的细胞核中，如透射电子显微镜与纳米金标记所示。FIZ 1和CRX从视网膜核提取物中与任一蛋白的抗体共沉淀。染色质免疫沉淀（ChIP）测定显示，FIZ 1是小鼠视网膜感光细胞内几种视杆细胞和视锥细胞基因启动子上蛋白复合物的一部分。FIZ 1与已知的NRL和CRX响应元件上的CRX或NRL复合，如通过使用FIZ 1抗体的电泳迁移率变动测定所示。FIZ 1可以直接结合CRX，如使用酵母双杂交和GST下拉测定所证明的。共转染测定表明，FIZ 1增加视蛋白测试启动子的CRX介导的激活。定量ChIP分析显示，与未成熟（P-3）神经视网膜相比，成年（P-25）神经视网膜中FIZ 1与视紫红质启动子的关联增加。与未成熟的视网膜相比，在成年神经视网膜中视紫红质基因（Rho）内转录活性RNA聚合酶-II的量显著增加。FIZ 1直接与CRX相互作用以增强CRX对靶基因的反式激活活性。在发育过程中，在神经视网膜组织中，FIZ 1与CRX靶基因的关联增加对应于Rho基因内转录活性Pol-II的关联增加。与以前的研究结果一起，我们的研究结果表明，FIZ 1可能作为光感受器特异性基因的转录共调节因子，由至少两个光感受器特异性转录因子CRX和NRL招募。进一步的研究正在进行中，以阐明FIZ 1在光感受器基因表达，发育和维持中的确切作用。
FIZ1 (Flt-3 Interacting Zinc-finger) is a broadly expressed protein of unknown function. We reported previously that in the mammalian retina, FIZ1 interacts with NRL (Neural-Retina Leucine-zipper), an essential transcriptional activator of rod photoreceptor-specific genes. The concentration of FIZ1 in the retina increases during photoreceptor terminal maturation, when two key transcription factors NRL and CRX (Cone-Rod Homeobox) become detectable on the promoters of photoreceptor-specific genes (i.e. Rhodopsin, Pde6b). To determine if FIZ1 is involved in regulating CRX-mediated transcriptional activation, we examined FIZ1 subcellular location in mouse neural retina, its ability to interact with CRX, and its association with CRX/NRL target genes. FIZ1 is present in the nucleus of adult photoreceptors as well as other retinal neurons as shown by transmission electron microscopy with nano-gold labeling. FIZ1 and CRX were co-precipitated from retinal nuclear extracts with antibodies to either protein. Chromatin immunoprecipitation (ChIP) assays revealed that FIZ1 is part of the protein complex on several rod and cone gene promoters, within photoreceptor cells of the mouse retina. FIZ1 complexes with CRX or NRL on known NRL- and CRX-responsive elements, as shown by electrophoretic mobility shift assays with FIZ1 antibody. FIZ1 can directly bind to CRX, as demonstrated using yeast two-hybrid and GST pull-down assays. Co-transfection assays demonstrated that FIZ1 increases CRX-mediated activation of Opsin test promoters. Quantitative ChIP analysis revealed an increased association of FIZ1 with the Rhodopsin promoter in adult (P-25) neural retina versus immature (P-3) neural retina. The quantity of transcriptionally active RNA Polymerase-II within the Rhodopsin gene (Rho) was significantly increased in the adult neural retina, compared to the immature retina. FIZ1 directly interacts with CRX to enhance CRX's transactivation activity for target genes. Developmentally, in neural retina tissue, the increased association of FIZ1 with CRX target genes corresponds to an increased association of transcriptionally active Pol-II within the Rho gene. Together with previous findings, our results suggest that FIZ1 may act as a transcriptional co-regulator of photoreceptor-specific genes, recruited by at least two photoreceptor-specific transcription factors, CRX and NRL. Further studies are underway to elucidate the exact role of FIZ1 in photoreceptor gene expression, development and maintenance.
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