Genome-wide mechanisms and dynamics of ATP-dependent chromatin remodeling complexes

ATP依赖性染色质重塑复合物的全基因组机制和动力学

基本信息

  • 批准号:
    10371166
  • 负责人:
  • 金额:
    $ 10万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT The SWI/SNF family ATP-dependent chromatin remodelers are multi-subunit protein complexes that dynamically position chromosomal nucleosomes to modulate DNA accessibility, transcription-factor binding, and cell-type-specific gene expression. SWI/SNF function is crucial at several stages of mammalian development, and recent human whole-genome and exome sequencing studies revealed striking mutational frequencies in genes encoding SWI/SNF subunits across a range of diseases - from neurologic disorders to over 20% of all cancers. Disease-associated SWI/SNF mutations often cause the loss of a protein subunit that further destabilizes the complex and results in altered subunit composition and functions. Of note, heterogeneity in SWI/SNF subunit composition is also observed naturally within and across cell types, hypothesized to result in complex- and tissue-specific SWI/SNF functions. Despite their importance, how these subunits determine the substrate preference and mechanistic functions of SWI/SNF complexes are not well understood, largely due to the lack of robust approaches to characterize where they bind within the genome and how they interact with chromatin genome-wide. Thus, the main goal of this proposal is to address this key knowledge gap. Since chromatin remodelers directly interact with nucleosomes, it is important to clarify remodeler-bound nucleosome compositions and structures. Standard biochemical characterization of soluble components purified from cellular extracts cannot determine the nucleosome structures associated with chromatin-bound complexes. It is also important to understand the kinetic parameters of remodeler-chromatin interactions, such as how fast a remodeler is recruited to its target sites, and how long does it remain bound at its genomic sites. The candidate proposes to address these questions by using structural and functional epigenomics approaches and live-cell single-molecule imaging, to characterize remodeler-chromatin interactions in the context of the complex and dynamic chromatin environment inside cells. Aim 1 is to determine the genome-wide occupancy of SWI/SNF complexes with distinct subunit compositions. Aim 2 is to determine a) the structures and histone composition of remodeler-bound nucleosomes genome-wide, and b) the kinetic parameters of remodeler-chromatin interactions in live cells. Aim 3 is to study the interaction of SWI/SNF with repressive chromatin. The mentored phase of this project will be completed under the sponsorship of Dr. Steven Henikoff at the Fred Hutchinson Cancer Research Center. The candidate will acquire training in live-cell single-molecule imaging under the supervision of Dr. Sheila Teves at the University of British Columbia. The proposed research and training will provide a strong foundation for the candidate to develop as an independent investigator, studying chromatin remodeling mechanisms and dynamics in the regulation of fundamental cellular processes.
项目总结/文摘

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CUT&RUN Profiling of the Budding Yeast Epigenome.
Epigenome Regulation by Dynamic Nucleosome Unwrapping.
  • DOI:
    10.1016/j.tibs.2019.09.003
  • 发表时间:
    2020-01
  • 期刊:
  • 影响因子:
    13.8
  • 作者:
    Brahma, Sandipan;Henikoff, Steven
  • 通讯作者:
    Henikoff, Steven
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Sandipan Brahma其他文献

Sandipan Brahma的其他文献

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{{ truncateString('Sandipan Brahma', 18)}}的其他基金

Genome-wide mechanisms and dynamics of ATP-dependent chromatin remodeling complexes
ATP依赖性染色质重塑复合物的全基因组机制和动力学
  • 批准号:
    10799754
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:
Genome-wide mechanisms and dynamics of ATP-dependent chromatin remodeling complexes
ATP依赖性染色质重塑复合物的全基因组机制和动力学
  • 批准号:
    10216103
  • 财政年份:
    2021
  • 资助金额:
    $ 10万
  • 项目类别:

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