New Inv. Award: Developing single-cell isoform sequencing tools to explore the diversity and regulation of alternative splicing in haematopoiesis

新库存

基本信息

  • 批准号:
    BB/P022073/1
  • 负责人:
  • 金额:
    $ 92.59万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2017
  • 资助国家:
    英国
  • 起止时间:
    2017 至 无数据
  • 项目状态:
    已结题

项目摘要

The cell is a fundamental unit of biology - all multicellular organisms consist of populations of billions, even trillions of cells - many of which will have differing functions within the organism. The diversity of cell function arises from the ability of the cell to regulate and orchestrate the repertoire of genes those cells express. One key mechanism cells use to increase the complexity of this repertoire is a process called alternative splicing. This is a regulated process where, during the process of gene expression, genetic information can be selectively excised from messenger RNA molecules. This can result in the generation of multiple protein variants from a single gene, and often these variants can have functionally distinct roles in the cell. It is by this means that the functional complexity of over 20,000 protein coding genes in the human genome can be increased by a factor of 5-10 - so from a relatively small number of genes, a larger variety of gene expression and function is possible. Recent advances in DNA sequencing technology have enabled researchers to study the genetic information - RNA, DNA and epigenetic modifications to the DNA - contained within single cells. This has allowed a totally new perspective on the complexity and diversity of cell types that make up an organism. These techniques are broadly applicable to different organisms, and in human health and disease. However, to date, little has been done to explore the nature of alternative splicing in single cells, in spite of the important role this process plays in normal development of plants, animals and humans, and indeed in human diseases such as cancer.In this proposal, we seek to generate new approaches that will reveal not just the extent of alternative splicing in single cells, and small populations of cells, but give parallel insight into the regulation of this process. While the methods we develop could be applied to almost any multicellular organism, we will use the technique to explore these processes in the development of normal blood cells in the mouse. We have previously developed methods for parallel analysis of the genomes and transcriptomes of single cells, and further developed these methods to include epigenetic information - in the form of DNA methylation. By expanding these methods to work with so-called "long read" sequencing technology, we will create a platform which allows us to read out the full complement of splicing variation in individual cells. In parallel we will be able to explore how alternative splicing might be regulated by DNA methylation.By using normal blood cell development as a testing ground for this new technology, we will reveal for the first time the amount of variation in alternative splicing in small populations of cells and single cells for which the function is very well understood. This information will be useful in enhancing our understanding of how blood stem cells make decisions, and how this complex system can sustain the generation of billions of new cells every day. Furthermore, by looking at cells from young and aged mice we will examine how the use of alternative splicing changes with age in these cells.
细胞是生物学的基本单位-所有多细胞生物体都由数十亿甚至数万亿个细胞组成-其中许多细胞在生物体内具有不同的功能。细胞功能的多样性源于细胞调节和协调这些细胞表达的基因库的能力。细胞用来增加这一功能复杂性的一个关键机制是一种称为选择性剪接的过程。这是一个受调控的过程,在基因表达过程中,遗传信息可以选择性地从信使RNA分子中切除。这可能导致从单个基因产生多个蛋白质变体,并且这些变体通常在细胞中具有功能上不同的作用。通过这种方式,人类基因组中超过20,000个蛋白质编码基因的功能复杂性可以增加5-10倍-因此,从相对较少的基因数量,可以实现更大范围的基因表达和功能。DNA测序技术的最新进展使研究人员能够研究单细胞中包含的遗传信息- RNA,DNA和DNA的表观遗传修饰。这使得人们对构成生物体的细胞类型的复杂性和多样性有了全新的认识。这些技术广泛适用于不同的生物体,以及人类健康和疾病。然而,迄今为止,几乎没有做过探索单细胞中选择性剪接的性质,尽管这个过程在植物,动物和人类的正常发育中起着重要作用,实际上在人类疾病如癌症中起着重要作用。在这个提议中,我们寻求产生新的方法,不仅揭示单细胞和小细胞群体中选择性剪接的程度,但同时也对这一过程的调节给予了深入的了解。虽然我们开发的方法可以应用于几乎任何多细胞生物,但我们将使用该技术来探索小鼠正常血细胞发育中的这些过程。我们以前已经开发了用于单细胞基因组和转录组的平行分析的方法,并进一步开发了这些方法,以包括表观遗传信息-以DNA甲基化的形式。通过将这些方法扩展到所谓的“长读”测序技术,我们将创建一个平台,使我们能够读出单个细胞中剪接变异的完整互补序列。与此同时,我们将能够探索DNA甲基化如何调节选择性剪接,通过使用正常血细胞发育作为这项新技术的试验场,我们将首次揭示小细胞群和单个细胞中选择性剪接的变异量,其功能已经非常清楚。这些信息将有助于提高我们对造血干细胞如何做出决定的理解,以及这个复杂的系统如何维持每天数十亿个新细胞的产生。此外,通过观察来自年轻和老年小鼠的细胞,我们将研究这些细胞中选择性剪接的使用如何随年龄而变化。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bacterial single-cell genomics enables phylogenetic analysis and reveals population structures from in vitro evolutionary studies
细菌单细胞基因组学能够进行系统发育分析,并通过体外进化研究揭示种群结构
  • DOI:
    10.1101/2020.08.25.266213
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Bawn M
  • 通讯作者:
    Bawn M
Automated Purification of DNA Origami with SPRI Beads
  • DOI:
    10.1002/smll.202308776
  • 发表时间:
    2023-12-06
  • 期刊:
  • 影响因子:
    13.3
  • 作者:
    Chau,Chalmers;Mohanan,Gayathri;Walti,Christoph
  • 通讯作者:
    Walti,Christoph
Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons
  • DOI:
    10.1101/2023.08.20.553715
  • 发表时间:
    2023-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Andrew M. Bell;Charlotte Utting;A. Dickie;M. Kucharczyk;Raphaëlle Quillet;M. Gutierrez-Mecinas;Aimi N B Razlan;A. Cooper;Yuxuan Lan;J. Hachisuka;Greg A Weir;K. Bannister;Masahiko Watanabe;Artur Kania;M. Hoon;I. Macaulay;Franziska Denk;A. Todd
  • 通讯作者:
    Andrew M. Bell;Charlotte Utting;A. Dickie;M. Kucharczyk;Raphaëlle Quillet;M. Gutierrez-Mecinas;Aimi N B Razlan;A. Cooper;Yuxuan Lan;J. Hachisuka;Greg A Weir;K. Bannister;Masahiko Watanabe;Artur Kania;M. Hoon;I. Macaulay;Franziska Denk;A. Todd
Single-cell genomics reveals population structures from in vitro evolutionary studies of Salmonella.
  • DOI:
    10.1099/mgen.0.000871
  • 发表时间:
    2022-09
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Bawn, Matt;Hernandez, Johana;Trampari, Eleftheria;Thilliez, Gaetan;Quince, Christopher;Webber, Mark A.;Kingsley, Robert A.;Hall, Neil;Macaulay, Iain C.
  • 通讯作者:
    Macaulay, Iain C.
A low-cost pipeline for soil microbiome profiling.
  • DOI:
    10.1002/mbo3.1133
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Bollmann-Giolai A;Giolai M;Heavens D;Macaulay I;Malone J;Clark MD
  • 通讯作者:
    Clark MD
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Iain Macaulay其他文献

Establishment of lympho-myeloid restricted progenitors prior to the emergence of definitive hematopoietic stem cells
  • DOI:
    10.1016/j.exphem.2013.05.049
  • 发表时间:
    2013-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Charlotta Böiers;Michael Lutteropp;Sidinh Luc;Petter Woll;Adam Mead;Anne Hultquist;Joana Carrelha;Iain Macaulay;Gemma Swiers;Luca Melchiori;Tiago Luis;Shabnam Kharazi;Tiphaine Bouriez-Jones;Qiaolin Deng;Annica Pontén;Christina Jensen;Ewa Sitnicka;Rickard Sandberg;Marella de Bruijn;Sten Eirik Jacobsen
  • 通讯作者:
    Sten Eirik Jacobsen
Embryonic thymopoiesis is initiated by an immune-restricted lympho-myeloid progenitor, independently of notch signaling
  • DOI:
    10.1016/j.exphem.2017.06.281
  • 发表时间:
    2017-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tiago Luis;Sidinh Luc;Takuo Mizukami;Hanane Boukarabila;Supat Thongjuea;Petter Woll;Emanuele Azzoni;Alice Giustacchini;Michael Lutteropp;Tiphaine Bouriez-Jones;Harsh Vaidya;Adam Mead;Deborah Atkinson;Charlotta Boiers;Joana Carrelha;Iain Macaulay;Roger Patient;Frederic Geissmann;Claus Nerlov;Rickard Sandberg
  • 通讯作者:
    Rickard Sandberg
3098 – SINGLE-CELL ANALYSIS OF ALTERNATIVE SPLICING IN HEMATOPOIETIC STEM AND PROGENITOR CELLS
  • DOI:
    10.1016/j.exphem.2021.12.315
  • 发表时间:
    2021-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Laura Mincarelli;Vladimir Uzun;Anita Scoones;Stuart Rushworth;Wilfred Haerty;Iain Macaulay
  • 通讯作者:
    Iain Macaulay
2010 - Perivascular Niche Cells Sense Thrombocytopenia and Activate Platelet-Biased Hscs in an IL-1 Dependent Manner
  • DOI:
    10.1016/j.exphem.2018.06.049
  • 发表时间:
    2018-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tiago C. Luis;Nikolaos Barkas;Alice Giustacchini;Bishan Wu;Tiphaine Bouriez-Jones;Iain Macaulay;Claus Nerlov;Sten Eirik Jacobsen
  • 通讯作者:
    Sten Eirik Jacobsen
PERIVASCULAR NICHE CELLS SENSE THROMBOCYTOPENIA AND ACTIVATE PLATELET-BIASED STEM CELLS IN AN IL-1 DEPENDENT MANNER
  • DOI:
    10.1016/j.exphem.2019.06.402
  • 发表时间:
    2019-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tiago Luis;Nikolas Barkas;Alice Giustacchini;Jose Guerrero;Bishan Wu;Tiphaine Bouriez-Jones;Iain Macaulay;Adam Mead;Claus Nerlov;Cedric Ghevaert;Sten Eirik Jacobsen
  • 通讯作者:
    Sten Eirik Jacobsen

Iain Macaulay的其他文献

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{{ truncateString('Iain Macaulay', 18)}}的其他基金

SCAnDi: Single-cell and single molecule analysis for DNA identification
SCAnDi:用于 DNA 鉴定的单细胞和单分子分析
  • 批准号:
    ES/Y010655/1
  • 财政年份:
    2024
  • 资助金额:
    $ 92.59万
  • 项目类别:
    Research Grant
Identifying unique regulatory elements related to polymorphic imprinting and gestational aging in the placenta
识别与胎盘多态印记和妊娠衰老相关的独特调节元件
  • 批准号:
    BB/V016210/1
  • 财政年份:
    2022
  • 资助金额:
    $ 92.59万
  • 项目类别:
    Research Grant
Defining mechanisms of CD8+ T-cell mediated immunity - using an integrated longitudinal model to achieve an elusive goal.
定义 CD8 T 细胞介导的免疫机制 - 使用集成纵向模型来实现难以捉摸的目标。
  • 批准号:
    BB/S017178/1
  • 财政年份:
    2020
  • 资助金额:
    $ 92.59万
  • 项目类别:
    Research Grant

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  • 批准号:
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  • 财政年份:
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  • 批准号:
    10307548
  • 财政年份:
    2018
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    $ 92.59万
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    10520054
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inv(16)急性髓性白血病的机制
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Analysis of Inv gene functions by generation of novel transgenic mice.
通过生成新型转基因小鼠分析 Inv 基因功能。
  • 批准号:
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支持有关投资的共同决策的决策辅助的可行性测试
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Identification of leukemia-initiating cells in an inv(3)(q21q26) mouse model
inv(3)(q21q26) 小鼠模型中白血病起始细胞的鉴定
  • 批准号:
    26670463
  • 财政年份:
    2014
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    $ 92.59万
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    Grant-in-Aid for Challenging Exploratory Research
Analysis of Initiating Events in Inv(16) Associated Acute Myeloid Leukemia
Inv(16) 相关急性髓系白血病起始事件分析
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    8734665
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