Dynamic association of NUP98 with the human genome.
Dynamic association of NUP98 with the human genome.
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DOI：
10.1371/journal.pgen.1003308
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Hetzer MW
中科院分区：
文献类型：
--
作者：
Liang Y;Franks TM;Marchetto MC;Gage FH;Hetzer MW
发育基因表达程序的忠实执行发生在多个层面，涉及许多不同的组分，例如转录因子、组蛋白修饰酶和mRNA加工蛋白。近期的证据表明，核孔蛋白——众所周知的控制核质运输的组分，在发育基因调控中具有广泛的功能，这些功能可能超出了它们在核运输中的作用。核孔蛋白在转录调控中这一意想不到的作用最初在真菌和果蝇中被描述，它是否也适用于人类细胞尚不清楚。在此，我们在全基因组水平上表明，核孔蛋白NUP98与人类胚胎干细胞分化过程中活跃的发育调控基因相关联。NUP98显性负性片段的过表达会降低NUP98结合基因的表达水平。此外，我们确定了NUP98调控发育基因的两种模式，这两种模式通过NUP98靶基因的空间定位来区分。处于发育诱导初始阶段的基因可与位于核周边核孔内的NUP98结合。或者，高度诱导的基因可在核内部与远离核孔的NUP98相互作用。这项工作首次证明NUP98在分化过程中与人类基因组动态关联，揭示了核孔蛋白在调控发育基因表达程序中的作用。
像人类这样的多细胞生物的发育需要根据分化阶段适当地激活基因表达程序。许多直接调控这一过程的蛋白质已被确定，包括组蛋白修饰酶和转录因子。核孔蛋白是构成核膜中唯一介导核运输的通道的蛋白质，它们是否在人类等高等生物中调控发育基因调控尚不清楚。在此我们表明，一种核孔蛋白在人类细胞分化过程中具有基因调控作用，这为核孔蛋白与发育相关且不依赖运输的功能提供了见解。我们发现核孔蛋白以一种与发育阶段紧密相关的动态方式与人类基因组相互作用。此外，操纵核孔蛋白的功能水平会破坏与其相关的发育基因的表达。我们的结果表明，核孔蛋白在细胞分化过程中与基因组发生功能性相互作用，揭示了人类发育基因调控的又一层面。
Faithful execution of developmental gene expression programs occurs at multiple levels and involves many different components such as transcription factors, histone-modification enzymes, and mRNA processing proteins. Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation. Overexpression of a dominant negative fragment of NUP98 levels decreases expression levels of NUP98-bound genes. In addition, we identify two modes of developmental gene regulation by NUP98 that are differentiated by the spatial localization of NUP98 target genes. Genes in the initial stage of developmental induction can associate with NUP98 that is embedded in the nuclear pores at the nuclear periphery. Alternatively, genes that are highly induced can interact with NUP98 in the nuclear interior, away from the nuclear pores. This work demonstrates for the first time that NUP98 dynamically associates with the human genome during differentiation, revealing a role of a nuclear pore protein in regulating developmental gene expression programs. Development of multicellular organisms such as humans requires appropriate activation of gene expression programs according to stages of differentiation. Many proteins that directly regulate this process have been identified, including histone-modifying enzymes and transcription factors. It is not clear whether nuclear pore proteins, proteins that form the only channels in the nuclear envelope that mediate nuclear transport, regulate developmental gene regulation in higher organisms such as humans. Here we show that one nuclear pore protein has a role in gene regulation during human cell differentiation, providing insight into the development-related and transport-independent function of nuclear pore proteins. We have found that the nuclear pore protein interacts with the human genome in a dynamic manner that is tightly linked to the developmental stage. In addition, manipulating the functional levels of the nuclear pore protein can disrupt expression of the developmental genes it associates with. Our results suggest that the nuclear pore protein functionally interacts with the genome during cell differentiation, uncovering an additional layer of developmental gene regulation in humans.
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DOI：
10.1083/jcb.123.6.1671
发表时间：
1993-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Belmont AS;Zhai Y;Thilenius A
通讯作者：
Thilenius A
影响因子：
3.3
作者：
Griffis, ER;Altan, N;Powers, MA
通讯作者：
Powers, MA
影响因子：
21.3
作者：
Brown, KE;Amoils, S;Fisher, AG
通讯作者：
Fisher, AG
影响因子：
7.8
作者：
Kehat, Izhak;Accornero, Federica;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.
影响因子：
56.9
作者：
Kosak, ST;Skok, JA;Singh, H
通讯作者：
Singh, H