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

机译：同源域转录程序所需的增强子-matrin-3网络相互作用

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摘要

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 Pitl-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.%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。
机译：30年前描述的同源结构域蛋白作为靶基因表达的调节剂在发育中起着至关重要的作用。然而，同源域因子转录活性的分子机制仍知之甚少。在这里，对发育所需的POU同源域转录因子Pit1（也称为Pou1f1）的调查显示，出乎意料的是，Pitl占据的增强子与富含核matrin-3的核网络/结构的结合是有效激活的关键事件Pit1调节的增强子/编码基因转录程序的图示。此绑定事件需要与Satb1（参考文献8）和β-catenin关联的Pit1。人PIT1（R271W）中自然发生的显性负点突变，导致垂体激素联合缺乏症，导致Pit1与β-catenin和Satb1的结合丧失，从而导致富含Matrin-3的网络，从而阻断了Pit1依赖性增强子/编码靶基因的激活。可以通过将突变体R271W Pit1蛋白人工束缚到matrin-3网络上，而无需与β-catenin和Satb1进行必要的关联来人工挽救这种有缺陷的激活。 Matrin-3网络连接的R271W Pit1突变体，而不是不受束缚的蛋白质，恢复了Pit1依赖的增强子激活和共激活子的募集，以p300为例，引起增强子RNA转录和靶基因激活。因此，这些研究揭示了靶基因调节增强子区域中意料之外的同源域因子/β-连环蛋白/ Satb1依赖性定位至亚核结构的结构，这是增强子结合的同源域因子有效激活发育基因转录程序的基础机制。在此研究中，Michael Rosenfeld及同事发现，被Pit1合并的增强子与核结构成分matmatrin-3和Satb1发生相互作用，而此过程中，％POU同源域转录因子Pit1是脑垂体发育所需的。这些实验显示了亚核架构蛋白在发育中基因的激发中所起的一个未曾预料到的结构。

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  • 来源
    《Nature》 |2014年第7521期|257-261a2|共6页
  • 作者

    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;

  • 作者单位

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA,The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

    Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;

    Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;

    Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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