Programmed DNA Elimination in Parasitic Nematodes

寄生线虫中的程序性 DNA 消除

基本信息

批准号：
10682424
负责人：
Jianbin Wang
金额：
$ 51.68万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682424
关键词：
3-Dimensional Architecture Area Ascaris Biological Biological Process Cell Cycle Cell Lineage Centromere Cessation of life Child Chromatin Chromosomal Breaks Chromosome Breakage Chromosome Structures Chromosomes Complex DNA DNA Double Strand Break DNA Replication Timing DNA biosynthesis Deposition Development Disease Drug Targeting Epigenetic Process Event Evolution Excision Exhibits Family suidae Future Generations Gene Expression Regulation Gene Silencing Generations Genes Genetic Transcription Genome Genomic Segment Genomics Health Human Invertebrates Kinetochores Location Longevity Maintenance Manuscripts Maps Mitosis Molecular Molecular Biology Morbidity - disease rate Nuclear Nucleotides Organism Parasitic nematode Persons Physiological Processes Positioning Attribute Preparation Process Public Health RNA Research Resected Site Somatic Cell Specific qualifier value Stress System Testis Toxocara Toxocariasis United States Variant Vertebrates Work chromosomal location ds-DNA flexibility genetic information genome integrity genome-wide healing improved insight new therapeutic target novel recruit repaired replication stress segregation socioeconomic development telomere tool

项目摘要

Project Summary/Abstract Ascaris remains a significant health problem in many parts of the world, infecting close to a billion people, many of them children, leading to significant morbidity. The related parasitic nematode Toxocara, causing human toxocariasis, also is increasingly being recognized as a significant public health problem in the United States. These parasitic nematodes undergo a novel form of genome re-organization, known as programmed DNA elimination. Very little is known regarding the function and molecular mechanisms of this DNA elimination process. Our recent work provides fundamental insights into this process demonstrating that DNA elimination is a conserved process in a group of parasitic nematodes serving to silence germline-expressed genes, particularly testis-specific genes, through their elimination in the somatic cells. Furthermore, we defined how holocentric chromosomes are dynamically re-organized to determine chromosomes regions that will be kept or eliminated. During Ascaris DNA elimination, DNA double-strand breaks are required to generate chromosomal fragments that will be eliminated. We identified 72 telomere addition sites where the presumed chromosomal breaks occur. These sites exhibit high fidelity in different somatic cell lineages and worms constrained within 3- 6 kb genomic regions and are called chromosomal breakage regions. Our analysis did not identify any specific sequence, structural features or common epigenetic factors that might specify or recruit molecular machinery to these regions. However, a prominent feature for these break regions is they become more chromatin accessible just before DNA elimination. Open chromatin is often a result of molecular processes that access the genome, including DNA replication and RNA transcription. In this proposal, we hypothesize that RNA transcription, R-loops, and/or DNA replication stress, as well as the three-dimensional genome organization may contribute to the key DNA breaks that initiate DNA elimination. We will examine these hypotheses in three specific aims: (1). Define when DNA break and telomere addition occurs during the cell cycle that leads to a DNA elimination mitosis; (2). Define DNA replication timing and stress, RNA transcription, and R-loops during DNA elimination; and (3). Map the 3D genome organization of the break regions. In addition to an understanding of the molecular mechanisms of the DNA breaks for Ascaris DNA elimination, the proposed studies will provide new information and insights into parasitic nematode chromosomes and chromatin organization, RNA transcription, DNA replication, DNA breaks and end resection, and telomere healing. Insights into these biological processes may identify novel molecular processes that could be potential drug targets in parasitic nematodes.

项目摘要/摘要在世界许多地方，阿斯卡里斯仍然是一个重大的健康问题，感染了近十亿人口，他们中的许多孩子，导致了明显的发病率。相关的寄生线虫toxocara，导致人类毒素病，越来越多地被公认为是曼联的重大公共卫生问题国家。这些寄生的线虫经历了一种新型的基因组重组形式，称为编程消除DNA。关于这种DNA消除的功能和分子机制知之甚少过程。我们最近的工作提供了对这一过程的基本见解，证明了消除DNA 是一组寄生线虫中的保守过程，用于沉默生殖线的基因，特别是睾丸特异性基因，通过它们在体细胞中的消除。此外，我们定义了如何全心染色体会动态重新组织以确定将保留或淘汰。在消除Ascaris DNA期间，DNA双链断裂需要产生染色体将要消除的碎片。我们确定了72个端粒位点，其中假定的染色体发生休息。这些位点在约束3-的不同体细胞谱系和蠕虫中表现出很高的保真度 6 kb基因组区域，称为染色体断裂区域。我们的分析没有确定任何特定的可能指定或募集分子机械的序列，结构特征或常见的表观遗传因子到这些地区。但是，这些突破区域的突出特征是它们变得更加染色质在消除DNA之前可以访问。开放染色质通常是分子过程的结果基因组，包括DNA复制和RNA转录。在此提案中，我们假设RNA 转录，R环和/或DNA复制应力以及三维基因组组织可能有助于启动DNA消除的关键DNA断裂。我们将在三个中检查这些假设具体目的：（1）。定义何时发生DNA断裂和端粒添加在导致A的细胞周期中 DNA消除有丝分裂；（2）。定义DNA复制时间和应力，RNA转录和R环在消除DNA；（3）。映射断裂区域的3D基因组组织。除了理解DNA的分子机制以消除Ascaris DNA的破裂，该提议研究将为寄生线虫染色体和染色质提供新的信息和见解组织，RNA转录，DNA复制，DNA断裂和最终切除以及端粒愈合。对这些生物过程的见解可能会鉴定出可能是潜在药物的新分子过程寄生线虫中的靶标。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Programmed DNA elimination: silencing genes and repetitive sequences in somatic cells.

DOI：
10.1042/bst20190951
发表时间：
2021-11-01
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
通讯作者：

The nematode Oscheius tipulae as a genetic model for programmed DNA elimination.

DOI：
10.1016/j.cub.2022.10.043
发表时间：
2022-12-05
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Dockendorff, Thomas C.;Estrem, Brandon;Reed, Jordan;Simmons, James R.;Zadegan, Sobhan Bahrami;Zagoskin, Maxim V.;Terta, Vincent;Villalobos, Eduardo;Seaberry, Erin M.;Wang, Jianbin
通讯作者：
Wang, Jianbin

Genomics of the Parasitic Nematode Ascaris and Its Relatives.