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Nature:与亚核结构相关的增强子激发

摘要 : 美国霍华德•休斯医学研究所的研究人员在近日的一项中,揭示亚核架构蛋白在发育基因的激发中所起的一个未曾预料到的结构。相关文章发表于2014年8月3日的《Nature》杂志上。
β-catenin和SATB1对PIT1靶点转录的影响

β-catenin和SATB1对PIT1靶点转录的影响

POU 同源域转录因子Pit1是脑垂体发育所需的。在这项研究中,Michael Rosenfeld及同事发现,被Pit1占据的增强子与核架构成分matrin-3 和Satb1发生相互作用,而这一联系是被Pit1调控的基因的激发所需的。

Pit1所发生的一个与疾病相关的突变会破坏与matrin-3网络的相互作用,导致转录活性的丧失。这些实验显示了亚核架构蛋白在发育基因的激发中所起的一个未曾预料到的结构。

原文摘要:

Required enhancer–matrin-3 network interactions for a homeodomain transcription program

Dorota Skowronska-Krawczyk, Qi Ma, Michal Schwartz, Kathleen Scully, Wenbo Li, Zhijie Liu, Havilah Taylor, Jessica Tollkuhn, Kenneth A. Ohgi, Dimple Notani, Yoshinori Kohwi,Terumi Kohwi-Shigematsu & Michael G. Rosenfeld

Homeodomain proteins, described 30 years ago, exert essential roles in development as regulators of target gene expression; however, the molecular mechanisms underlying transcriptional activity of homeodomain factors remain poorly understood. Here investigation of a developmentally required POU-homeodomain transcription factor, Pit1 (also known as Pou1f1), has revealed that, unexpectedly, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer/coding gene transcriptional program. Pit1 association with Satb1 (ref. 8) and β-catenin is required for this tethering event. A naturally occurring, dominant negative, point mutation in human PIT1(R271W),causing combined pituitary hormone deficiency, results in loss of Pit1 association with β-catenin and Satb1 and therefore the matrin-3-rich network, blocking Pit1-dependent enhancer/coding target gene activation. This defective activation can be rescued by artificial tethering of the mutant R271W Pit1 protein to the matrin-3 network, bypassing the pre-requisite association with β-catenin and Satb1 otherwise required. The matrin-3 network-tethered R271W Pit1 mutant, but not the untethered protein, restores Pit1-dependent activation of the enhancers and recruitment of co-activators, exemplified by p300, causing both enhancer RNA transcription and target gene activation. These studies have thus revealed an unanticipated homeodomain factor/β-catenin/Satb1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.

 

对应Nature杂志: 2014年10月9日Nature杂志精选

来源: Nature中文 浏览次数:77

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