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Functional significance and remodeling challenges of polyploidy across the lifetime of epithelial tissues

上皮组织整个生命周期中多倍体的功能意义和重塑挑战

基本信息

批准号：
BB/V002392/1
负责人：
Andre Pires Da Silva
金额：
$ 68.4万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV002392%2F1
关键词：
Functional significance remodeling challenges polyploidy

项目摘要

Animal cells have characteristic structures that support their biological roles. For example, epithelial cells adhere tightly to their neighbors to form sheets of tissue, a structure that supports barrier functions such as with the skin as an outer protective layer, or the lining of the gut. One aspect of cell structure is the nucleus and its size. While most cells are diploid, with a copy of the genome from each parent, certain cells become polyploid, with many copies of the genome within a single nucleus. This leads to large nuclei and proportionately large cells. What are the benefits and costs of polyploidy?Polyploid cells occur in the liver, muscles, and maternal and extra-embryonic tissues, such as those that support placental development at the mother-fetus interface. Benefits include barrier tissue maintenance and repair after wounding. Wound repair involves polyploid cells becoming even larger to help cover the wound site. Also, having many copies of the genome supports rapid, efficient production of needed proteins, such as from placental genes that promote maternal milk production. However, there is not always a clear correlation between DNA copy number and actual protein output, and under experimental conditions some tissues seem to also function without being polyploid. Thus, investigation of additional tissue types is needed to better understand the hypothesized benefits of polyploidy.On the other hand, polyploidy also poses challenges to cells. In some cases, the entire cell's genome is not copied, but only DNA regions containing certain genes. This is an efficient way to support rapid production when only the specific proteins from those genes are needed. Yet, this partial increase in DNA copies is an unstable arrangement that usually triggers programmed cell death, known as apoptosis, as a form of biological quality control. Polyploid cells therefore require special genetic properties to suppress this. One key research system where this has been explored is the fruit fly Drosophila melanogaster, a powerful genetics model species. However, we discovered that critical genes for controlling programmed cell death, the so-called Grim Reaper genes, are a unique feature in flies. It remains unknown which genes serve this function in other animals. Also, one hallmark of cancer cells is that they have unstable DNA arrangements yet somehow evade programmed cell death. Research in new species on how polyploid cells handle the programmed cell death issue will identify critical genes and could help improve our understanding of genetics relevant to cancer treatment.In this research project, we will test the hypothesized benefits (barrier tissue structure, rapid protein production) and examine the potential risks (unstable DNA arrangement, need to block cell death) of polyploidy in a novel biological system: the two extra-embryonic tissues of the flour beetle Tribolium castaneum. These tissues serve epithelial barrier functions by surrounding and protecting the embryo. The serosa surrounds the embryo and yolk while the amnion, like its namesake in mammals, forms a fluid-filled, inner cavity. The serosa also has a rapid production role to make a cuticle layer that reinforces the eggshell. Notably, these tissues are stable and polyploid for most of their lifetime, and then they actively uncover the embryo and precisely undergo cell death. We have developed methods to investigate polyploidy in the beetle, including genome sequencing and live imaging microscopy that reveals healthy and experimentally perturbed barrier tissue structure. The serosa and amnion offer an excellent comparative system. Our preliminary work suggests that the serosa is capable of increased polyploidy to compensate in genetic models of wound-like tissue impairment while the amnion is not. This paves the way to better understanding of tissue-specific features of polyploidy and to uncover new critical genes involved in polyploidy control.

动物细胞具有支持其生物学作用的特征结构。例如，上皮细胞紧密地附着在相邻的组织上，形成一层组织，这种结构支持屏障功能，如将皮肤作为外部保护层，或肠道的内层。细胞结构的一个方面是细胞核及其大小。虽然大多数细胞是二倍体，父母双方都有基因组的副本，但某些细胞变成了多倍体，单个细胞核中有许多基因组副本。这导致了较大的细胞核和比例较大的细胞。多倍体的好处和代价是什么？多倍体细胞存在于肝脏、肌肉、母体组织和胚胎外组织中，例如那些在母胎界面支持胎盘发育的组织。好处包括屏障组织的维护和受伤后的修复。伤口修复涉及多倍体细胞变得更大，以帮助覆盖伤口部位。此外，拥有多个基因组拷贝有助于快速、高效地生产所需的蛋白质，例如来自促进母体产奶的胎盘基因。然而，DNA拷贝数和实际蛋白质产量之间并不总是有明确的相关性，在实验条件下，一些组织似乎也在发挥作用，而不是多倍体。因此，需要对更多的组织类型进行研究，以更好地理解多倍体的假设好处。另一方面，多倍体也对细胞构成挑战。在某些情况下，整个细胞的基因组不会被复制，而是只复制包含某些基因的DNA区域。当只需要这些基因中的特定蛋白质时，这是一种支持快速生产的有效方法。然而，DNA拷贝的这种部分增加是一种不稳定的安排，通常会触发被称为细胞凋亡的程序性细胞死亡，作为生物质量控制的一种形式。因此，多倍体细胞需要特殊的遗传特性来抑制这种现象。探索这一点的一个关键研究系统是果蝇，一种强大的遗传学模式物种。然而，我们发现，控制细胞程序性死亡的关键基因，即所谓的死神基因，是苍蝇的一个独特特征。目前还不清楚哪些基因在其他动物身上起到了这种作用。此外，癌细胞的一个特点是它们的DNA排列不稳定，但却以某种方式逃避了细胞程序性死亡。在新物种中研究多倍体细胞如何处理程序性细胞死亡问题将识别关键基因，并有助于提高我们对癌症治疗相关遗传学的理解。在这项研究项目中，我们将测试多倍体在一个新的生物系统中的假设好处(屏障组织结构，快速蛋白质生产)和潜在风险(不稳定的DNA排列，需要阻止细胞死亡)：面粉甲虫的两个胚胎外组织。这些组织通过包围和保护胚胎发挥上皮屏障功能。浆膜包裹着胚胎和卵黄，而羊膜，就像哺乳动物中的同名羊膜一样，形成了一个充满液体的内腔。浆膜还具有快速生产的作用，可以形成强化蛋壳的角质层。值得注意的是，这些组织在其一生的大部分时间里都是稳定的多倍体组织，然后它们积极地揭开胚胎并准确地经历细胞死亡。我们已经开发了研究甲虫多倍体的方法，包括基因组测序和实时成像显微镜，揭示了健康和实验上受到干扰的屏障组织结构。浆膜和羊膜提供了一个很好的比较系统。我们的初步工作表明，在创伤样组织损伤的遗传模型中，浆膜能够增加多倍体来补偿，而羊膜则不是。这为更好地理解多倍体的组织特异性特征和发现涉及多倍体控制的新的关键基因铺平了道路。