Understanding the Role of Nucleosome Turnover in the Malaria Parasite

了解核小体周转在疟疾寄生虫中的作用

基本信息

批准号：
8515919
负责人：
Karine Gaelle Le Roch
金额：
$ 36.25万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515919
关键词：
Address Affect Antimalarials Binding Biological Cell Cycle ChIP-seq Chromatin Chromatin Remodeling Factor Chromatin Structure Communicable Diseases Complex DNA Data Set Detection Development Digestion Epigenetic Process Erythrocytes Eukaryota Figs - dietary Formaldehyde Gene Expression Gene Expression Profile Gene Expression Regulation Genetic Transcription Genome Goals Histones Infection Life Cycle Stages Malaria Maps Mass Spectrum Analysis Measures Messenger RNA Metabolic stress Methods Methylation Micrococcal Nuclease Molecular Molecular Profiling Narration Nucleosomes Nucleotides Parasite Control Parasites Pathogenicity Pattern Perception Plasmodium falciparum Play Ploidies Positioning Attribute Post-Translational Protein Processing Process Processed Genes Proteins Regulatory Element Research Resolution Role Series Site Staging Techniques Technology Testing Transcriptional Regulation Ubiquitination Work base functional genomics genome sequencing genome-wide histone methyltransferase next generation sequencing novel therapeutics programs promoter public health relevance research study response transcription factor ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Malaria remains one of the most deadly infectious diseases in the world. To identify new therapeutic strategies, we must gain a comprehensive understanding of how the malaria parasite regulates its complex life cycle. The goal of this proposal is to elucidate the mechanisms that orchestrate chromatin restructuring. More specifically, we explore whether nucleosome positioning, occupancy and turnover direct developmental programs over the course of the parasite infectious cycle. There is growing evidence that the epigenetic state of chromatin plays a role in parasite gene expression and pathogenicity. Whereas histone levels in most eukaryotes remain fairly constant across the cell cycle, we have found a "histone crash" precisely at the most transcriptionally active stage of the parasite erythrocytic cycle. Accordingly, we hypothesize that the unique manner in which P. falciparum regulates histone turnover and positioning may control the parasite gene expression in a specific manner. Using two complementary methods, we will measure histone-free and histone-bound DNA content across the parasite life cycle. DNA-enriched regions will be analyzed using next generation sequencing technology (Illumina(R)). Results will generate maps of "open" and "closed" chromatin regions that will be correlated with steady state mRNA patterns. To determine whether histone post-translational modifications regulate histone turnover, we will use a mass spectrometry approach. Stage-specific histone marks will be validated by ChIP-seq experiments. Further mass spectrometry and functional genomic studies will then be used to determine the chromatin-remodeling complexes that are involved in regulating histone turnover. Using these independent data sets, we seek to explore a connection between histone positioning, histone post-translational modifications and the parasite transcriptome. Revealing the molecular mechanisms that control histone turnover will not only allow us to find new ways to interfere with waves of transcriptional expression but will also transform our perceptions of the molecular mechanisms controlling the parasite transcription at the chromatin level and provide signposts for new anti-malarial therapies. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to elucidate the mechanisms that orchestrate chromatin restructuring. The proposed research explores whether nucleosome positioning, occupancy and turnover direct developmental programs over the course of the parasite infectious cycle.

描述（由申请人提供）：疟疾仍然是世界上最致命的传染病之一。为了确定新的治疗策略，我们必须对疟原虫如何调节其复杂的生命周期有一个全面的了解。该提案的目的是阐明编排染色质重组的机制。更具体地说，我们探索核小体定位，占用和周转直接发育计划是否在寄生虫感染周期中。越来越多的证据表明，染色质的表观遗传状态在寄生虫基因表达和致病性中起作用。大多数真核生物中的组蛋白水平在整个细胞周期中仍然相当恒定，但我们发现“组蛋白崩溃”正是在寄生虫红细胞周期的最转录活性阶段的“组蛋白崩溃”。因此，我们假设恶性疟原虫调节组蛋白更新和定位的独特方式可能以特定方式控制寄生虫基因的表达。使用两种互补方法，我们将在整个寄生虫生命周期中测量无组蛋白和组蛋白结合的DNA含量。将使用下一代测序技术（Illumina（R））分析富含DNA的区域。结果将生成与稳态mRNA模式相关的“开放”和“封闭”染色质区域的地图。为了确定组蛋白的翻译后修饰是否调节组蛋白更新，我们将使用质谱法。特异性组蛋白标记将通过CHIP-SEQ实验验证。然后，将使用进一步的质谱和功能基因组研究来确定与调节组蛋白更新有关的染色质复制复合物。使用这些独立的数据集，我们试图探索组蛋白定位，组蛋白后翻译后修饰与寄生虫转录组之间的联系。揭示控制组蛋白更新的分子机制，不仅将使我们能够找到新的方法来干扰转录表达的波，而且还将改变我们对控制染色质水平上寄生虫转录的分子机制的看法，并为新的抗马里尔疗法提供了路标。公共卫生相关性：该提案的目的是阐明编排染色质重组的机制。拟议的研究探讨了在寄生虫感染周期中，核小体定位，占用和离职直接发育计划是否直接发育计划。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Strand-Specific RNA-Seq Applied to Malaria Samples.

链特异性 RNA 测序应用于疟疾样本。

DOI：
10.1007/978-1-0716-0743-5_2
发表时间：
2021
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Lu,XueqingMaggie;LeRoch,Karine
通讯作者：
LeRoch,Karine

Targeting the Plasmodium ubiquitin/proteasome system with anti-malarial compounds: promises for the future.

DOI：
10.2174/187152610791163345
发表时间：
2010-05
期刊：
Infectious disorders drug targets
影响因子：
0
作者：
D. D. Chung-D.;K. L. Le Roch
通讯作者：
D. D. Chung-D.;K. L. Le Roch

Characterization of the ubiquitylating components of the human malaria parasite's protein degradation pathway.

DOI：
10.1371/journal.pone.0043477
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Chung DW;Ponts N;Prudhomme J;Rodrigues EM;Le Roch KG
通讯作者：
Le Roch KG

PuFFIN--a parameter-free method to build nucleosome maps from paired-end reads.

DOI：
10.1186/1471-2105-15-s9-s11
发表时间：
2014
期刊：
BMC bioinformatics
影响因子：
3
作者：
Polishko A;Bunnik EM;Le Roch KG;Lonardi S
通讯作者：
Lonardi S

Dynamic and Combinatorial Landscape of Histone Modifications during the Intraerythrocytic Developmental Cycle of the Malaria Parasite.

DOI：
10.1021/acs.jproteome.6b00366
发表时间：
2016-08-05
期刊：
Journal of proteome research
影响因子：
4.4
作者：
Saraf A;Cervantes S;Bunnik EM;Ponts N;Sardiu ME;Chung DW;Prudhomme J;Varberg JM;Wen Z;Washburn MP;Florens L;Le Roch KG
通讯作者：
Le Roch KG