Coordinated genomic control of ciliogenesis and cell movement by RFX2.
Coordinated genomic control of ciliogenesis and cell movement by RFX2.
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DOI：
10.7554/elife.01439
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发表时间：
2014
期刊：
影响因子：
7.7
通讯作者：
Wallingford JB
中科院分区：
文献类型：
--
作者：
Chung MI;Kwon T;Tu F;Brooks ER;Gupta R;Meyer M;Baker JC;Marcotte EM;Wallingford JB
将基因表达的系统水平程序与体内离散细胞生物学过程联系起来的机制仍然知之甚少。在这项研究中，我们已经为多纤毛上皮细胞（MCCs）定义了这样一个程序，MCCs是一种对气道，大脑和生殖道的正常发育和稳态至关重要的细胞类型。从纤毛相关转录因子Rfx 2的基因组分析开始，我们使用生物信息学和体内细胞生物学方法来深入了解纤毛组装和功能的分子基础。此外，我们发现了一个以前未认识到的作用，在细胞运动的Rfx因子，发现Rfx 2细胞自主控制在新生的MCCs顶端表面扩张。因此，Rfx 2协调MCCs中多种不同的基因表达程序，调节控制细胞运动、纤毛发生和纤毛功能的基因。因此，这项工作作为一个范例，了解基因组控制的细胞生物学过程，从早期细胞形态发生事件的终端分化的细胞功能。DOI：http://dx.doi.org/10.7554/eLife.01439.001细胞表面有数百个微小的毛发状结构，称为纤毛，在我们的呼吸道、大脑和生殖系统中起着重要作用。通过以协调的方式跳动，纤毛使流体沿特定方向流动。这些多纤毛细胞的发育是一个复杂的过程，其中基因表达为蛋白质，这种基因表达受称为转录因子的其他蛋白质的调节。在无脊椎动物中，纤毛的发育受来自RFX家族的转录因子控制，RFX家族似乎对脊椎动物中纤毛的发育也很重要。然而，这一过程的细节，特别是参与其中的基因的身份以及它们的功能是如何相互关联的，在脊椎动物中还没有得到很好的理解。Chung等人试图通过分析脊椎动物中由转录因子Rfx 2控制其表达的基因网络来解决这一问题。结果表明，Rfx 2控制的基因涉及纤毛的各个方面，包括已知在异常纤毛引起的疾病中突变的几个基因。Chung等人还鉴定了以前认为与纤毛无关的基因。由于多纤毛细胞正在发育，但在它们能够产生纤毛之前，它们必须首先从上皮细胞的底部迁移到这一层的顶部。Chung等人发现Rfx 2也参与了这一过程。Chung等人采取的方法-包括RNA序列分析、染色体上Rfx 2结合位点的检测、蛋白质相互作用的计算预测和体内细胞成像的组合，可用于对其他发育和生物学过程进行类似的系统水平分析。DOI：http://dx.doi.org/10.7554/eLife.01439.002网站
The mechanisms linking systems-level programs of gene expression to discrete cell biological processes in vivo remain poorly understood. In this study, we have defined such a program for multi-ciliated epithelial cells (MCCs), a cell type critical for proper development and homeostasis of the airway, brain and reproductive tracts. Starting from genomic analysis of the cilia-associated transcription factor Rfx2, we used bioinformatics and in vivo cell biological approaches to gain insights into the molecular basis of cilia assembly and function. Moreover, we discovered a previously un-recognized role for an Rfx factor in cell movement, finding that Rfx2 cell-autonomously controls apical surface expansion in nascent MCCs. Thus, Rfx2 coordinates multiple, distinct gene expression programs in MCCs, regulating genes that control cell movement, ciliogenesis, and cilia function. As such, the work serves as a paradigm for understanding genomic control of cell biological processes that span from early cell morphogenetic events to terminally differentiated cellular functions. DOI: http://dx.doi.org/10.7554/eLife.01439.001 Cells that have hundreds of tiny hair-like structures called cilia on their surface have important roles in our airways and also in the brain and reproductive system. By beating in a coordinated manner, the cilia cause fluid to flow in a particular direction. The development of these multiciliated cells is a complex process in which genes are expressed as proteins, with this gene expression being regulated by other proteins called transcription factors. In invertebrates the development of the cilia is controlled by transcription factors from the RFX family, which also appear to be important for development of cilia in vertebrates. However, the details of this process—in particular, the identities of the genes that are involved and how their functions are related—are not well understood in vertebrates. Chung et al. have sought to remedy this by analyzing the network of genes whose expression is controlled by the transcription factor Rfx2 in vertebrates. The results showed that the genes controlled by Rfx2 were involved in all aspects of cilia, including several genes that are known to be mutated in diseases caused by abnormal cilia. Chung et al. also identified genes that were not previously thought to be relevant to cilia. As multiciliated cells are developing, but before they can generate cilia, they must first migrate from the bottom of the epithelium, the layer of tissue in which they function, to the top of this layer. Chung et al. found that Rfx2 was also involved in this process. The approach taken by Chung et al.—which involved a combination of RNA sequence analysis, examination of Rfx2 binding sites on chromosomes, computational predictions of protein interactions and in vivo cellular imaging—could be used to perform similar systems-level analyses of other developmental and biological processes. DOI: http://dx.doi.org/10.7554/eLife.01439.002