How do a conserved family of RNA binding proteins protect the transcriptome from aberrant processing?

RNA 结合蛋白的保守家族如何保护转录组免受异常处理?

基本信息

  • 批准号:
    BB/W002019/1
  • 负责人:
  • 金额:
    $ 61.66万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

PURPOSE OF RESEARCH: Gene expression requires correct production of mature protein-coding RNAs (mRNAs) by RNA processing. This includes splicing, which joins parts of the gene called "exons" and removes others called "introns". RNA processing is guided by short RNA sequences. This project seeks identify the mechanism how RBMXL2 and RBMX proteins suppress use of "cryptic" RNA processing sequences that would otherwise corrupt productive gene expression. This project addresses three current knowledge gaps. Firstly, how long exons are efficiently recognised during mRNA maturation is currently poorly understood, yet critically important for expression of key genes, including mouse Meioc (required for meiotic prophase) and human BRCA2 (a tumour suppressor needed for genome stability). In particular, how cryptic RNA processing events are repressed within long exons is very poorly understood, yet may underpin problems associated with deficiency of RBMX family proteins (male infertility, genome instability and Shashi intellectual disability syndrome). Thirdly, how RBMX proteins repress splice sites is unknown. Since repressed RNA processing sites were the majority of targets we identified in our preliminary screens, this suggests that repression is the primary mechanism of action of RBMXL2 and RBMX proteins.TIMELINESS AND VALUE FOR MONEY: This project is timely since (1) We have already made and carried out initial characterisation of an RBMXL2 knockout mouse. This mouse is male infertile and has already enabled us to identify some cryptic splice sites repressed by RBMXL2. (2) Through collaboration with two world leading groups based in Edinburgh (Prof Ian Adams and Prof Donal O'Carroll) we will be able to purify the exact cell types that arrest in our RBMXL2 knockout mouse and use these for RNA sequencing analyses. (3) Providing value for money, the O'Carroll group will provide us with a mouse line that expresses GFP during meiosis at no charge other than shipping. This line will enable ~99% purification of cells in meiosis from RBMXL2 knockout mice that we can then characterise. (4) Providing extra value for money, this project will make use of a capillary gel electrophoresis system that was recently purchased by a grant from the Pathological Society and matching funds from Newcastle University. (5) We have already identified novel cryptic RNA processing sites that are repressed by RBMX in somatic cells and carried out experiments to globally identify RBMX binding sites in human cells (currently in the sequencing queue of our Genomics Core Facility). OUTCOMES: We expect that the results of this project will be significant in understanding how the splicing and polyadenylation machineries enable proper RNA processing of long exons, and avoid including cryptic exons. We expect to identify patterns of gene expression that depend on RBMXL2 during male meiosis, improving understanding of the causes of male infertility. Since our preliminary study has already detected RBMX target genes in cancer cells that are important for how cells respond to genotoxic drugs, our research may lead to new strategies to increase the efficacy of chemotherapy. The main beneficiaries from this work will be scientists and students who will be trained, other scientists interested in gene expression, members of the public that we will engage, and possibly in the longer term patients who are treated with genotoxic drugs.
研究目的:基因表达需要通过RNA加工正确产生成熟的蛋白质编码RNA(mRNA)。这包括剪接,它连接基因的一部分称为“外显子”,并删除其他称为“内含子”。RNA加工由短RNA序列指导。该项目旨在确定RBMXL2和RBMX蛋白如何抑制使用“神秘”RNA加工序列的机制,否则这些序列会破坏生产性基因表达。该项目解决了目前的三个知识差距。首先,在mRNA成熟过程中有效识别多长外显子目前知之甚少,但对于关键基因的表达至关重要,包括小鼠Meioc(减数分裂前期所需)和人类BRCA 2(基因组稳定性所需的肿瘤抑制因子)。特别是,隐藏的RNA加工事件如何在长外显子内被抑制的了解非常少,但可能会导致与RBMX家族蛋白缺乏相关的问题(男性不育,基因组不稳定性和Shashi智力障碍综合征)。第三,RBMX蛋白如何抑制剪接位点是未知的。由于抑制的RNA加工位点是我们在初步筛选中鉴定的大多数靶点,这表明抑制是RBMXL2和RBMX蛋白的主要作用机制。时间性和金钱价值:该项目是及时的,因为(1)我们已经制作并进行了RBMXL2敲除小鼠的初步表征。这只小鼠是雄性不育的,并且已经使我们能够鉴定出一些被RBMXL2抑制的隐蔽剪接位点。(2)通过与位于爱丁堡的两个世界领先的研究小组(Ian亚当斯教授和Donal O'Carroll教授)的合作,我们将能够纯化在我们的RBMXL 2敲除小鼠中停滞的确切细胞类型,并将其用于RNA测序分析。(3)提供物有所值,奥卡罗尔集团将为我们提供一个小鼠线,表达GFP在减数分裂期间在不收取运费以外。该细胞系将能够从RBMXL2敲除小鼠中纯化约99%的减数分裂细胞,然后我们可以将其纯化。(4)提供额外的价值,该项目将利用毛细管凝胶电泳系统,这是最近购买的赠款从病理学会和匹配的资金从纽卡斯尔大学。(5)我们已经确定了体细胞中被RBMX抑制的新型隐蔽RNA加工位点,并进行了实验以全面确定人类细胞中的RBMX结合位点(目前在我们基因组学核心设施的测序队列中)。结果:我们期望该项目的结果将在理解剪接和多聚腺苷酸化机制如何使长外显子的适当RNA加工,并避免包括隐藏的外显子方面具有重要意义。我们希望确定在男性减数分裂过程中依赖RBMXL2的基因表达模式,从而提高对男性不育原因的理解。由于我们的初步研究已经在癌细胞中检测到RBMX靶基因,这些基因对细胞如何对遗传毒性药物作出反应很重要,我们的研究可能会导致增加化疗疗效的新策略。这项工作的主要受益者将是将接受培训的科学家和学生,对基因表达感兴趣的其他科学家,我们将参与的公众成员,以及可能接受遗传毒性药物治疗的长期患者。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
ST3Gal1 synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer
  • DOI:
    10.1101/2023.04.03.535346
  • 发表时间:
    2023-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Rebecca Garnham;D. Geh;Ryan Nelson;Erik Ramon-Gill;L. Wilson;Edward N Schmidt;Laura Walker;Beth Adamson;A. Buskin;A. Hepburn;Kirsty Hodgson;Hannah Kendall;F. Frame;N. Maitland;Kelly Coffey;C. Robson;D. Elliott;R. Heer;Matthew S Macauley;J. Munkley;L. Gaughan;J. Leslie;E. Scott
  • 通讯作者:
    Rebecca Garnham;D. Geh;Ryan Nelson;Erik Ramon-Gill;L. Wilson;Edward N Schmidt;Laura Walker;Beth Adamson;A. Buskin;A. Hepburn;Kirsty Hodgson;Hannah Kendall;F. Frame;N. Maitland;Kelly Coffey;C. Robson;D. Elliott;R. Heer;Matthew S Macauley;J. Munkley;L. Gaughan;J. Leslie;E. Scott
Epithelial specific splicing regulator proteins as emerging oncogenes in aggressive prostate cancer.
  • DOI:
    10.1038/s41388-023-02838-9
  • 发表时间:
    2023-10
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Advani, Rahul;Luzzi, Sara;Scott, Emma;Dalgliesh, Caroline;Weischenfeldt, Joachim;Munkley, Jennifer;Elliott, David J.
  • 通讯作者:
    Elliott, David J.
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David Elliott其他文献

Prospective memory in the red zone: Cognitive control and capacity sharing in a complex, multi-stimulus task.
红色区域的预期记忆:复杂的多刺激任务中的认知控制和能力共享。
  • DOI:
    10.1037/xap0000224
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    L. Strickland;David Elliott;M. D. Wilson;S. Loft;A. Neal;A. Heathcote
  • 通讯作者:
    A. Heathcote
Exploring Research Priorities of Parents Who Have Children With Down Syndrome, Cleft Lip With or Without Cleft Palate, Congenital Heart Defects, or Spina Bifida Using ConnectEpeople: A Social Media Coproduction Research Study
使用 ConnectEpeople 探索孩子患有唐氏综合症、唇裂伴或不伴腭裂、先天性心脏病或脊柱裂的父母的研究重点:一项社交媒体合作研究
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    M. Sinclair;J. McCullough;David Elliott;A. Latos;P. Braz;C. Cavero;Anna Jamry;A. João Santos;L. Páramo
  • 通讯作者:
    L. Páramo
An institutional experience with laparoscopic gastric bypass complications seen in the first year compared with open gastric bypass complications during the same period.
与同期开放式胃绕道手术并发症相比,第一年出现的腹腔镜胃绕道手术并发症的机构经验。
  • DOI:
    10.1016/s0002-9610(02)00829-2
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    3
  • 作者:
    C. See;P. Carter;David Elliott;P. Mullenix;William E Eggebroten;C. Porter;D. Watts
  • 通讯作者:
    D. Watts
A simple reproducible technique for the retrieval of broken proximal femoral blades, a technical note and review of literature
  • DOI:
    10.1016/j.jcot.2019.10.003
  • 发表时间:
    2020-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mohamed A. Imam;Ziad Harb;David Elliott
  • 通讯作者:
    David Elliott
HOXA gene expression defines definitive fetal hematopoietic cells differentiated from hESCs
  • DOI:
    10.1016/j.exphem.2015.06.056
  • 发表时间:
    2015-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Elizabeth Ng;Lisa Azzola;Freya Bruveris;David Elliott;David Haylock;Susie Nilsson;Edouard Stanley;Andrew Elefanty
  • 通讯作者:
    Andrew Elefanty

David Elliott的其他文献

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{{ truncateString('David Elliott', 18)}}的其他基金

Why is the highly conserved splicing regulator protein Tra2b essential for spermatogenesis?
为什么高度保守的剪接调节蛋白 Tra2b 对于精子发生至关重要?
  • 批准号:
    BB/S008039/1
  • 财政年份:
    2019
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Research Grant
Identifying the functions of a family of nuclear RNA binding proteins that switch expression between somatic and meiotic cells
鉴定在体细胞和减数分裂细胞之间切换表达的核 RNA 结合蛋白家族的功能
  • 批准号:
    BB/P006612/1
  • 财政年份:
    2017
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Research Grant
Deciphering the functions of the RNA binding protein T-STAR in mouse development
破译 RNA 结合蛋白 T-STAR 在小鼠发育中的功能
  • 批准号:
    BB/K018957/1
  • 财政年份:
    2013
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Research Grant
OCE-PRF: ZOOPREDICT - A study of ZOOPlankton Responses to Environmental Determinants with Interns, Classes, and Teachers
OCE-PRF:ZOOPREDICT - 一项关于 ZOOPlankton 对实习生、班级和教师环境决定因素的反应的研究
  • 批准号:
    1225817
  • 财政年份:
    2013
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Standard Grant
Functional characterisation of the evolutionarily conserved splicing regulator protein Tra2B in germ cell development
生殖细胞发育中进化保守剪接调节蛋白 Tra2B 的功能表征
  • 批准号:
    BB/I006923/1
  • 财政年份:
    2011
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Research Grant
A transgenic approach to investigate the RNA binding protein T-STAR
研究 RNA 结合蛋白 T-STAR 的转基因方法
  • 批准号:
    BB/D013917/1
  • 财政年份:
    2006
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Research Grant
Workshop in Nonlinear Control Theory, May 27-31, 1992, Washington University, St. Louis, MO
非线性控制理论研讨会,1992 年 5 月 27-31 日,华盛顿大学,密苏里州圣路易斯
  • 批准号:
    9204612
  • 财政年份:
    1992
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Standard Grant
Workshop on Neuroengineering; University of Maryland, October 25-27, 1992
神经工程研讨会;
  • 批准号:
    9223463
  • 财政年份:
    1992
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Standard Grant
Workshop on Aerospace Applications of Neurocontrol
神经控制航空航天应用研讨会
  • 批准号:
    9022539
  • 财政年份:
    1990
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Standard Grant
Paleoecology of Vertebrates from the Silurian and Devonian of the Canadian Arctic Island
加拿大北极岛志留纪和泥盆纪脊椎动物的古生态学
  • 批准号:
    8921819
  • 财政年份:
    1990
  • 资助金额:
    $ 61.66万
  • 项目类别:
    Continuing Grant

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Renewal application: How do ecological trade-offs drive ectomycorrhizal fungal community assembly? Fine- scale processes with large-scale implications
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  • 批准号:
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The Politics of Financial Citizenship - How Do Middle Class Expectations Shape Financial Policy and Politics in Emerging Market Democracies?
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Collaborative Research: How do plants control sperm nuclear migration for successful fertilization?
合作研究:植物如何控制精子核迁移以成功受精?
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