Repression of Six3 by a corepressor regulates rhodopsin expression
Repression of Six3 by a corepressor regulates rhodopsin expression
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DOI：
10.1073/pnas.0705878104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Manavathi, Bramanandam;Peng, Shaohua;Kumar, Rakesh
在这里，我们提供了功能获得、功能丧失和分子证据，支持转移相关蛋白1 （MTA1）和Six3之间以及Six3和视紫红质之间的遗传相互作用。我们发现MTA1以组蛋白去乙酰酶依赖的方式与Six3染色质物理相互作用，导致Six3基因的转录抑制。MTA1也是Six3相互作用的协同抑制因子，有助于Six3对Six3转录的自我负向调节。相反，小鼠胚胎成纤维细胞中MTA1等位基因的缺失或大鼠视网膜神经节细胞中MTA1等位基因的敲低会刺激Six3的表达。MTA1缺失小鼠的MTA1失活导致Six3水平升高和视网膜细胞增殖，但眼睛形成无明显异常。然而，出乎意料的是，我们在mta1缺失小鼠的视网膜中发现了Six3向视紫质染色质的增强募集；Six3的同源克隆域与视紫红质启动子中的特定DNA元件相互作用，刺激其转录，导致视紫红质表达增加。此外，在全前脑畸形患者中，在同位结构域螺旋3中自然发生缺失突变的Six3蛋白不能与视紫红质DNA结合或刺激视紫红质转录，这意味着受影响的全前脑畸形患者的视紫红质途径可能存在缺陷。Six3与Crx或NRL合作刺激视紫红质-luc的转录。这些发现揭示了MTA1作为Six3上游修饰剂的作用，并表明Six3是视紫红质表达的直接刺激物，从而揭示了MTA1/Six3/视紫红质通路在脊椎动物眼睛中的推测作用。
Here, we provide gain-of-function, loss-of function, and molecular evidence supporting genetic interactions between metastasis associated protein 1 (MTA1) and Six3 and between Six3 and rhodopsin. We discovered that MTA1 physically interacts with the Six3 chromatin in a histone deacetylase-dependent manner, leading to transcriptional suppression of the Six3 gene. MTA1 is also a Six3-interacting corepressor that contributes to a self-negative regulation of Six3 transcription by Six3. In contrast, deletion of the MTA1 alleles in murine embryonic fibroblasts or its knockdown in rat retinal ganglion cells stimulates Six3 expression. MTA1 inactivation in the MTA1-null mice results in an elevated Six3 level and proliferation of the retina cells with no obvious abnormities in eye formation. However, unexpectedly, we discovered an enhanced recruitment of Six3 to the rhodopsin chromatin in retina from the MTA1-null mice; Six3's homeoclomain interacts with specific DNA elements in the rhodopsin promoter to stimulate its transcription, resulting in increased rhodopsin expression. Further, in holoprosencephaly patients, Six3 protein with a naturally occurring deletion mutation in the helix 3 of the homeodomain does not bind to rhodopsin DNA or stimulate rhodopsin transcription, implying a potential defective rhodopsin pathway in the affected holoprosencephaly patients. Further Six3 cooperates with Crx or NRL in stimulating transcription from the rhodopsin-luc. These findings reveal a previously unrecognized role for the MTA1 as an upstream modifier of Six3 and indicate that Six3 is a direct stimulator of rhodopsin expression, thus revealing a putative role for the MTA1/Six3/rhodopsin pathway in vertebrate eye.