Chromatin Diminution in Ascaris

蛔虫染色质减少

• 批准号: 8418686
• 负责人: RICHARD E. DAVIS
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418686
• 关键词: Address; Affect; Antibodies; Area; Ascaris; Ascaris suum; Biology; Caenorhabditis elegans; Cell division; Cell-Free System; Cells; Centromere; ChIP-seq; Chromatin; Chromosomal Breaks; Chromosome Breakage; Chromosome Segregation; Chromosomes; Complex; DNA; DNA Sequence; DNA Sequence Rearrangement; Development; Embryo; Employee Strikes; Epigenetic Process; Gene Expression; Gene Expression Profile; Gene Silencing; Generations; Genes; Genome; Human; Human Biology; Indirect Immunofluorescence; Individual; Kinetochores; Length; Location; Maintenance; Metaphase Plate; Methods; Mitosis; Molecular; Nematoda; Organism; Parasites; Parasitic nematode; Play; Process; Proteins; Public Health; RNA; Role; Site; Small RNA; Specific qualifier value; Staging; Surveys; System; Testing; Time; Tissues; Transfection; chromatin modification; chromosome loss; comparative; daughter cell; genome sequencing; histone modification; insight; male; new technology; novel strategies; pathogen; prevent; programs; role model; segregation; socioeconomics; tool

DESCRIPTION (provided by applicant): Genome maintenance and stability are essential, and an organism's genome rarely changes. In striking contrast, chromatin diminution is a programmed process that eliminates specific DNA sequences from the genome. In the parasitic nematode, Ascaris, 25% of the genome is eliminated in the somatic lineages during the 3rd through 5th cleavage (4 to 16 cell stage), while the germline genome remains intact. Both repetitive and unique sequences (genes) are lost during chromatin diminution. The elimination results in chromosome breakage and the loss of chromosome termini as well as the generation of new chromosomes. This process is thought to be a form of gene silencing necessary for development and germline establishment, yet how this programmed elimination contributes to the germline to somatic transition in early Ascaris development remains a mystery more than 100 years after it was discovered. Furthermore, the mechanisms for how chromosomal regions are targeted for elimination, where the sites of chromosomal breakage are located, how DNA breaks are made, what sequences are lost, and how specific sequences are selected to be lost or retained remain unknown. New technologies and approaches will be leveraged to exploit the unique biology and tools in Ascaris to examine chromatin diminution and define eliminated and re-arranged sequences, to examine chromatin modifications associated with diminution, to test a new hypothesis for how eliminated DNA is not segregated during cell division, and to gain additional insight into the potential role of small RNAs in chromatin diminution. We propose that a comprehensive comparison of the somatic and germline genome in Ascaris will permit us to address for the first time a number of central questions regarding diminution including: What rearrangements occur? What genes are lost? Are there common features among the breakpoints that provide insight into how the breakpoints are defined? Are the chromosomal breakpoints at the same approximate location in all individuals or do they vary in different individuals? Furthermore, we propose that epigenetic chromatin changes are associated with the process of diminution and that Ascaris 22G endo-siRNAs and the associated Argonaute CSR-1 RISC complex contribute to chromatin diminution by marking regions of Ascaris chromosomes for retention or elimination. Ascaris is an important human pathogen as it infects over a billion people. Understanding gene maintenance, alterations, and the role of alterations in gene expression in Ascaris is important in understanding the biology of this human parasite. Furthermore, understanding the molecular regulators, mechanism, and consequences of diminution will not only provide insight into DNA elimination and its importance in nematodes, but is likely to increase our understanding of this phenomenon and germline, chromosome, and genome biology in general.

描述（由申请人提供）：基因组维持和稳定性至关重要，生物体的基因组很少发生变化。在引人注目的对比中，染色质减小是一个编程过程，可消除基因组中的特定DNA序列。在寄生线虫中，阿斯卡里斯（Ascaris），在第3至第五裂段（4至16个细胞阶段）中，在体细胞谱系中消除了25％的基因组，而生殖线基因组仍然完好无损。在染色质减少期间，重复和独特的序列（基因）都丢失。消除导致染色体断裂和染色体末端的损失以及新染色体的产生。人们认为这一过程被认为是发展和种系建立所必需的基因沉默的一种形式，但是该程序的消除如何为早期阿斯卡里斯（Ascaris）发育中的躯体过渡的种系做出贡献，在发现它后100年以上。此外，染色体区域如何针对消除的机制，染色体断裂位置所在的位置，如何制作DNA的断裂，丢失了哪些序列以及如何丢失或保留的特定序列仍然未知。将利用新技术和方法来利用Ascaris中的独特生物学和工具来检查染色质的减少并定义消除和重新安排的序列，以检查与减少的染色质修饰，以测试与细胞分裂中消除DNA相关的新假设，以在细胞分裂中分离出来，以使Small RNAS的潜在small rnnas脱颖而出。我们建议对阿斯卡里斯的躯体和种系基因组进行全面比较，这将使我们首次解决有关减少的许多中心问题，包括：发生了什么重排？哪些基因丢失了？断点之间是否有共同的特征，可以洞悉如何定义断点？在所有个体中相同位置的染色体断点是在不同个体中的变化吗？此外，我们建议表观遗传染色质的变化与减少的过程有关，Ascaris 22G内多 - siRNA和相关的Argonaute CSR-CSR-1 RISC复合物通过标记assaris染色体的保留或消除的区域来促进染色质质量。阿斯卡里斯（Ascaris）是一种重要的人类病原体，因为它感染了十亿人。了解基因维持，改变以及改变基因表达在阿斯卡里斯中的作用对于理解这种人寄生虫的生物学很重要。此外，了解分子调节剂，减少的机制和后果不仅可以洞悉DNA消除及其在线虫中的重要性，而且很可能会增加我们对这种现象和种系，染色体，染色体和基因组生物学的理解。