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性。但是，要正确进行，我们的基因组需要以正确且适当的方式在空间上组织。为了维持这个空间组织，需要保持不活跃的小块DNA，并且我们的单元具有多台机器，这些机器旨在使这些转座的活性保持在检查中。未能失活的转座子会对我们的基因组的空间接线造成混乱的后果，并导致细胞身份的变化。我们最近确定了这些机器的新组件，称为ZMym2，该机器在我们的细胞中起着重要作用，从而使它们保持其身份。 ZMYM2功能的破坏会导致遗传遗传的肾脏疾病，并且与不同的蛋白质结合时也会导致癌症。关于该蛋白在分子水平上的功能知之甚少，在这里我们将填补这一知识差距。具体而言，我们将研究ZMYM2如何影响基因组的折叠和募集机器的募集，以使逆转录子沉默。我们还将研究ZMym2函数中“相分离”的现象。相位分离与何时以液态状态相关联，该状态有助于细胞过程的分区化。我们的发现对于通过抑制返回跨座子活性来理解如何维持细胞态将很重要。