Mechanisms of epigenetic gene regulation by the Drosophila COMPASS-like complex

果蝇COMPASS样复合体的表观遗传基因调控机制

基本信息

项目摘要

Developmental processes in eukaryotic cells are controlled by DNA elements called enhancers. The molecular nature of enhancers is not well understood, although current evidence suggests they differ from other DNA elements by having a distinct structure within the chromosomes. Structural differences can arise from enzymatic modification of the histone proteins responsible for packaging the DNA in the nucleus. This project focuses on studying the enzymes that modify enhancer elements and how their action helps turn on critical genes at the right time and location during development. The work will be carried out using a multi-disciplinary approach that combines genetic, biochemical and high-throughput bioinformatics tools in the fruit fly, Drosophila melanogaster, as the model organism. Because the mechanisms governing how, when and where genes are turned on and off during development are conserved across evolution, the results should have far-reaching impact, from yeast to humans. The project will have broad educational impact by providing students with training in multiple areas, including protein structure modeling, biochemistry, bioinformatics, genetics and advanced microscopy imaging. Students also learn how to develop scientific hypotheses, independently carry out experiments and interpret results, prepare oral and written summaries and publish their work, skills that provide a strong technical knowledge base for diverse scientific careers.The metazoan COMPASS related coactivator complexes catalyze the methylation of histone H3 on Lysine 4 (H3K4), epigenetic marks associated with controlling eukaryotic gene transcription. The Cmi/Trr COMPASS-like complex in Drosophila is responsible for monomethylating H3K4 and regulates enhancer activity in cooperation with transcription factors important for normal development. Trr provides histone methyltransferase activity, while Cmi contains plant homeodomain Zn fingers in two conserved clusters that co-evolved over 1.5 billion years with chromosome compaction in nucleosomes. Despite the conservation and importance in transcription control, it is not well understood how the COMPASS-like complexes are able to prime and maintain enhancer activities during development. This project focuses on the role of the conserved PHD finger domains in chromatin recognition and key cellular signaling pathways that depend on precise enhancer control. Taking advantage of the versatile Drosophila genetic model system, this project tests broad hypotheses (1) that the clustered PHD domains found in Cmi and homologous vertebrate proteins contribute essential epigenetic histone reader functions that drive the proper priming and regulation of gene enhancers and (2) the Drosophila COMPASS-like coactivator complex regulates the timing of enhancer utilization to integrate key developmental signals. One aim of this project explores the combined functions of the finger domains in the conserved PHD cluster that are essential for proper enhancer regulation. Structural modeling studies of the PHD finger domains and targeted mutagenesis, combined with in vitro and in vivo measurements of chromatin association, will define the histone recognition and binding properties of Cmi and mammalian PHD finger domains and further elucidate the mechanisms of enhancer control by the COMPASS-like complexes. A second aim incorporating developmental, genetic and molecular analyses (ChIP-seq, RNA-seq, chromatin capture) will expand our understanding of target gene regulation in vivo, help correlate specific enhancer epigenetic marks with COMPASS-like complex functions, and provide significant new insights regarding conserved mechanisms of chromatin regulation.
真核细胞的发育过程是由称为增强子的DNA元件控制的。 增强子的分子本质还不清楚,尽管目前的证据表明它们与其他DNA元件不同,在染色体内具有独特的结构。结构差异可由负责将DNA包装在细胞核中的组蛋白的酶促修饰引起。 该项目的重点是研究修饰增强子元素的酶,以及它们的作用如何帮助在发育过程中的正确时间和位置打开关键基因。这项工作将采用多学科方法进行,该方法将遗传、生物化学和高通量生物信息学工具结合在果蝇(Drosophila melanogaster)中作为模式生物。 由于在发育过程中,基因如何、何时、何地开启和关闭的机制在整个进化过程中是保守的,因此这些结果应该会产生深远的影响,从酵母到人类。 该项目将通过为学生提供多个领域的培训产生广泛的教育影响,包括蛋白质结构建模,生物化学,生物信息学,遗传学和先进的显微成像。 学生还学习如何提出科学假设、独立进行实验和解释结果、准备口头和书面总结并发表他们的工作,这些技能为不同的科学职业提供了强大的技术知识基础。后生动物COMPASS相关辅激活因子复合物催化组蛋白H3在赖氨酸4(H3 K4)上的甲基化,这是与控制真核基因转录相关的表观遗传标记。果蝇中的Cmi/Trr COMPASS样复合物负责H3 K4的单甲基化,并与对正常发育重要的转录因子合作调节增强子活性。Trr提供组蛋白甲基转移酶活性,而Cmi在两个保守簇中含有植物同源结构域Zn指,其与核小体中的染色体压实共同进化超过15亿年。尽管在转录控制中的保守性和重要性,但尚不清楚COMPASS样复合物如何能够在发育期间引发和维持增强子活性。该项目的重点是保守的PHD指结构域在染色质识别和关键的细胞信号转导途径,依赖于精确的增强子控制的作用。利用多功能的果蝇遗传模型系统,该项目测试了广泛的假设(1)在Cmi和同源脊椎动物蛋白中发现的成簇的PHD结构域贡献了必需的表观遗传组蛋白阅读器功能,其驱动基因增强子的适当启动和调节,以及(2)果蝇COMPASS样共激活因子复合物调节增强子利用的时间以整合关键发育信号。该项目的一个目的是探索保守的PHD簇中的指状结构域的组合功能,这些功能对于适当的增强子调控至关重要。PHD指结构域和靶向诱变的结构建模研究,结合体外和体内染色质缔合的测量,将定义Cmi和哺乳动物PHD指结构域的组蛋白识别和结合特性,并进一步阐明COMPASS样复合物控制增强子的机制。第二个目标结合发育,遗传和分子分析(ChIP-seq,RNA-seq,染色质捕获)将扩大我们对体内靶基因调控的理解,帮助将特异性增强子表观遗传标记与COMPASS样复杂功能相关联,并提供有关染色质调控保守机制的重要新见解。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Drosophila MLR COMPASS complex is essential for programming cis-regulatory information and maintaining epigenetic memory during development
果蝇 MLR COMPASS 复合体对于顺式调控信息编程和发育过程中维持表观遗传记忆至关重要
  • DOI:
    10.1093/nar/gkaa082
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Zraly, Claudia B;Zakkar, Abdul;Perez, John Hertenstein;Ng, Jeffrey;White, Kevin P;Slattery, Matthew;Dingwall, Andrew K
  • 通讯作者:
    Dingwall, Andrew K
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Andrew Dingwall其他文献

STUDIES ON CEREBROSPINAL FLUID: II. THE OCCURRENCE OF LEAD IN CEREBROSPINAL FLUID
  • DOI:
    10.1016/s0021-9258(18)75849-3
  • 发表时间:
    1933-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    I.M. Rabinowitch;Andrew Dingwall;F.H. Mackay
  • 通讯作者:
    F.H. Mackay

Andrew Dingwall的其他文献

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{{ truncateString('Andrew Dingwall', 18)}}的其他基金

Mechanisms of epigenetic gene regulation by the Drosophila COMPASS-like complex
果蝇COMPASS样复合体的表观遗传基因调控机制
  • 批准号:
    1413331
  • 财政年份:
    2014
  • 资助金额:
    $ 83.88万
  • 项目类别:
    Continuing Grant
Developmental Functions of SNR1 and the BRM Chromatin Remodeling
SNR1 的发育功能和 BRM 染色质重塑
  • 批准号:
    1122001
  • 财政年份:
    2011
  • 资助金额:
    $ 83.88万
  • 项目类别:
    Continuing Grant
Developmental Functions of SNR1 and the BRM Chromatin Remodeling Complex in Drosophila
果蝇中 SNR1 和 BRM 染色质重塑复合体的发育功能
  • 批准号:
    0818620
  • 财政年份:
    2008
  • 资助金额:
    $ 83.88万
  • 项目类别:
    Standard Grant
Developmental Functions of SNR1 and the BRM Chromatin Remodeling Complex in Drosophila
果蝇中 SNR1 和 BRM 染色质重塑复合体的发育功能
  • 批准号:
    0516386
  • 财政年份:
    2005
  • 资助金额:
    $ 83.88万
  • 项目类别:
    Standard Grant
Developmental Functions of SNR1 and the BRM Chromatin Remodeling Complex in Drosophila
果蝇中 SNR1 和 BRM 染色质重塑复合体的发育功能
  • 批准号:
    0439316
  • 财政年份:
    2004
  • 资助金额:
    $ 83.88万
  • 项目类别:
    Continuing Grant
Developmental Functions of SNR1 and the BRM Chromatin Remodeling Complex in Drosophila
果蝇中 SNR1 和 BRM 染色质重塑复合体的发育功能
  • 批准号:
    0221563
  • 财政年份:
    2002
  • 资助金额:
    $ 83.88万
  • 项目类别:
    Continuing Grant

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