Understanding the mechanisms that suppress the transcription of the non-coding genome

了解抑制非编码基因组转录的机制

基本信息

批准号：
BB/Y000617/1
负责人：
Andrew Sharrocks
金额：
$ 102.46万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FY000617%2F1
关键词：
Understanding mechanisms suppress transcription non

项目摘要

The decoding of our genome through the process of gene transcription ultimately dictates the form and activity of the cells in our body. However, for this to proceed correctly, our genome needs to be spatially organised in a correct and appropriate manner. To maintain this spatial organisation, small pieces of DNA known as transposons need to be kept inactive and our cells have several machines that are designed to keep the activity of these transposons in check. Failure to inactivate transposons can cause chaotic consequences for the spatial wiring of our genome and result in changes to cellular identity. We recently identified a new component of these machines known as ZMYM2 which plays an important role in our cells, allowing them to maintain their identity. Disruption of ZMYM2 function leads to genetically inherited kidney disorders and can also lead to cancer when combined with a different protein. Little is known about how this protein functions at the molecular level and here we will fill this knowledge gap. Specifically we will study how ZMYM2 affects the folding of the genome and the recruitment of machines that function to silence retrotransposons. We will also study the phenomenon of "phase separation" in ZMYM2 function. Phase separation relates to when molecules become associated in a liquid-like state that helps with compartmentalisation of cellular processes. Our findings will be important for understanding how cell states are maintained through the suppression of retrotransposon activity.

通过基因转录过程对我们的基因组进行解码最终决定了我们体内细胞的形式和活动。然而，为了使这一过程正确进行，我们的基因组需要以正确且适当的方式进行空间组织。为了维持这种空间组织，需要保持称为转座子的小 DNA 片段不活跃，并且我们的细胞有几台机器旨在控制这些转座子的活动。未能使转座子失活可能会对我们的基因组空间布线造成混乱的后果，并导致细胞身份的变化。我们最近发现了这些机器的一个新组件，称为 ZMYM2，它在我们的细胞中发挥着重要作用，使它们能够保持其身份。 ZMYM2 功能的破坏会导致遗传性肾脏疾病，与不同的蛋白质结合时还可能导致癌症。人们对这种蛋白质如何在分子水平上发挥作用知之甚少，在这里我们将填补这一知识空白。具体来说，我们将研究 ZMYM2 如何影响基因组折叠以及沉默反转录转座子机器的招募。我们还将研究ZMYM2函数中的“相分离”现象。相分离涉及分子何时以类液体状态结合，有助于细胞过程的区室化。我们的发现对于理解如何通过抑制逆转录转座子活性来维持细胞状态非常重要。