Epigenetic Encoding and Reprogramming in C. elegans

线虫的表观遗传编码和重编程

• 批准号: 8385022
• 负责人: William G. KELLY
• 金额: $ 23.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-20 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385022
• 关键词: Address; Adult; Affect; Amaze; Biomedical Research; Caenorhabditis elegans; Cell division; Cells; Child; Chromatin; Chromatin Structure; Defect; Development; Developmental Biology; Discrimination; Disease; Embryo; Embryonic Development; Epigenetic Process; Excision; Fertilization; Gametogenesis; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genome; Germ Cells; Germ Lines; Goals; Histones; Human; In Vitro; Inherited; Instruction; Investigation; Mutation; Nature; Oocytes; Parents; Pattern; Pluripotent Stem Cells; Process; Protocols documentation; Safety; Side; Site; Staging; Stem Cell Research; Stem cells; Techniques; Technology; Testing; Therapeutic; Tissues; Uncertainty; Vision; Work; cell type; embryo cell; genome-wide; induced pluripotent stem cell; meetings; mutant; offspring; pluripotency; programs; research study; scale up; sperm cell; stem cell technology; tool; zygote

DESCRIPTION (provided by applicant): The transcriptome that defines a differentiated cell type is strongly influenced by the chromatin structure imposed on the genome by epigenetic processes. This structural information becomes heritably stabilized, or programmed, as differentiation proceeds through the cell divisions required to build a tissue. The stability of ths information is revealed by the difficulties encountered when trying to reverse, or reprogram, a differentiated cell into a pluripotent stem cell state. Current strategies, such as induced pluripotent stem cell (iPS) technologies are amazing but inefficient, and the quality of the cells obtained is unclear. These problems are due the stochastic nature of uncontrolled processes involved in these reprogramming techniques. In contrast, the highly differentiated gamete genomes are quite efficiently and accurately reprogrammed when they meet in the zygote, creating a totipotent epigenome. Importantly, there is epigenetic information that arrives in the gametes, encoded in the parental germ line, which is not targeted for reprogramming. This information presumably contributes to the totipotency of the zygote and the continued immortality of the germline. Three questions are central to understanding these processes: 1) How is epigenetic information inherited through the gametes reprogrammed in the zygote?; 2) How does specific information avoid this fate to remain stable through generations?; and 3) How is discrimination between the appropriate targets for these different fates achieved? In this project, we will take advantage of the genetic and epigenetic tools available in C. elegans to identify targets of zygotic reprogramming. We will further identify epigenetic modifiers that participate in the parental programming and zygotic reprogramming mechanisms. We will test and adapt protocols to expand the analyses to a genome-wide approach. The longer-term goal is to use the information obtained by these experiments to identify the mechanisms that direct the programming and reprogramming machinery to the appropriate sites in the genome. This will ultimately guide therapies to interrupt or manipulate mechanisms that contribute to heritable epigenetic disease states, and identify strategies that will appropriately guide in vitro reprogramming to efficiently achieve a state compatible with therapeutic safety. PUBLIC HEALTH RELEVANCE: The genetic information that is passed from parent to child is accompanied by "epigenetic" information that can affect how genes behave in the offspring. Epigenetic information is encoded within the parental germline and packaged into the gametes. Some of this information is "reprogrammed" in the offspring when the gametes meet at fertilization; however, some of the encoded information is not reprogrammed and may contribute to totipotency-the ability of the fertilized egg to generate all tissues arising during embryonic development. We are working to understand the nature of this encoding process in the parent. We are also determining how some encoded information is reprogrammed in the embryo but other information remains heritable across many generations, and how discrimination between these classes of information is achieved.

描述（由申请人提供）：定义分化细胞类型的转录组受到表观遗传过程施加于基因组的染色质结构的强烈影响。这种结构信息变得遗传稳定，或编程，通过细胞分裂所需的分化过程中建立一个组织。当试图逆转或重编程分化细胞进入多能干细胞状态时遇到的困难揭示了这些信息的稳定性。目前的策略，如诱导多能干细胞（iPS）技术是惊人的，但效率低下，获得的细胞的质量是不清楚的。这些问题是由于这些重编程技术中涉及的不受控制的过程的随机性。相反，高度分化的配子基因组在受精卵中相遇时会非常有效和准确地重新编程，产生全能表观基因组。重要的是，在配子中有表观遗传信息，在亲本生殖系中编码，这不是重编程的目标。这一信息可能有助于受精卵的全能性和生殖细胞的持续永生。理解这些过程有三个核心问题：1）表观遗传信息是如何通过受精卵中的配子重编程遗传的？2)具体的信息如何避免这种命运，使其在几代人中保持稳定？以及3）如何区分这些不同命运的适当目标？在这个项目中，我们将利用C. elegans来识别合子重编程的目标。我们将进一步鉴定参与亲本编程和合子重编程机制的表观遗传修饰剂。我们将测试和调整方案，以将分析扩展到全基因组方法。长期目标是利用这些实验获得的信息来确定将编程和重编程机制引导到基因组中适当位点的机制。这将最终指导治疗中断或操纵有助于遗传性表观遗传疾病状态的机制，并确定适当指导体外重编程以有效实现与治疗安全性相容的状态的策略。 公共卫生关系：从父母传给孩子的遗传信息伴随着"表观遗传"信息，这些信息可以影响基因在后代中的行为。表观遗传信息在亲本种系中编码并包装到配子中。当配子在受精时相遇时，这些信息中的一部分在后代中被“重新编程”;然而，一些编码的信息没有被重新编程，可能有助于全能性受精卵在胚胎发育过程中产生所有组织的能力。我们正在努力了解父母这种编码过程的本质。我们还在确定一些编码信息是如何在胚胎中重新编程的，而其他信息在许多代中仍然是可遗传的，以及如何实现这些信息类别之间的区分。