Epigenetic and developmental regulation of embryonic plasticity and gametogenesis

胚胎可塑性和配子发生的表观遗传和发育调控

• 批准号: 10405973
• 负责人: Ryan Joseph Gleason
• 金额: $ 5.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405973
• 关键词: ATAC-seq; Address; Animal Model; Award; Biochemical; Bioinformatics; Biology; CRISPR/Cas technology; Caenorhabditis elegans; Cell Culture Techniques; Cell Lineage; Cell division; Cells; Chromatin; Coupled; Couples; DNA Sequence; Development; Developmental Biology; Embryo; Embryology; Embryonic Development; Epigenetic Process; Fertility; Fertilization; Foundations; Gametogenesis; Gene Expression; Genes; Genetic Transcription; Genomic approach; Genomics; Germ Cells; Goals; Heritability; Heterochromatin; Histone H3; Histones; Influentials; Inherited; Laboratories; Link; Maintenance; Malignant Neoplasms; Mammalian Cell; Mammals; Maps; Memory; Mentors; Modeling; Molecular; Molecular Chaperones; Nucleosomes; Organism; Pathway interactions; Phase; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Principal Investigator; Process; Regulation; Reproductive Biology; Research; Research Personnel; Resolution; Resources; Role; Series; Somatic Cell; System; Techniques; Testing; Training; Training Support; Undifferentiated; Universities; Variant; Whole Organism; Yeasts; blastomere structure; career; career development; chromatin remodeling; clinical application; design; developmental plasticity; embryonic stem cell; epigenetic regulation; epigenome; genetic approach; genome editing; genome-wide; histone modification; imaging approach; in vivo; insight; intergenerational; molecular carrier; novel; pluripotency; post-doctoral training; programs; stem cell therapy; transcription factor; transcriptome sequencing

Project Summary/Abstract: Early embryonic cells are pluripotent, possessing the transient capacity to generate all the cells of an organism. A fundamental question in developmental biology concerns identifying the epigenetic factors that underlie this temporary developmental plasticity, as well as understanding how commitment to a specific cell lineage is achieved and maintained. How embryonic pluripotency is established, and whether development coordinates the restriction of cellular plasticity with the acquisition of cell fate is poorly understood. Epigenetic phenomena refer to changes in gene expression and chromatin organization inherited through cell divisions without changing the underlying DNA sequences. Recently, studies during my postdoctoral research have uncovered an unappreciated developmental regulation of the incorporation of key molecular carriers of epigenetic information, the replication-coupled histone H3 and histone variant, H3.3, during gametogenesis that influences the epigenetic organization in the early embryo, with a lasting effect on pluripotency and lineage commitment. The goal of this Pathway to Independence Award proposal is to request support for training in order to develop expertise in, and to apply, genomic approaches while addressing the role of epigenetic regulation of plasticity during early embryonic development, as well as cell fate maintenance. K99/R00 support during this stage of my career will be transformative to my successful development as an independent researcher. The research plans and career development outlined in this proposal will take advantage of the extensive resources at Johns Hopkins University, as well as collaborate with leading experts in genomics and bioinformatics. This proposal will examine the epigenetic regulation and developmental timing of early embryonic plasticity. Specifically, during the K99 mentored phase of this award the principal investigator (PI) will combine current expertise and preliminary results generated during postdoctoral training at Johns Hopkins University, with newly developed techniques developed in the collaborator's laboratories to answer fundamental questions regarding the dynamic epigenetic mechanisms underlying embryonic plasticity and cell fate restriction. This approach promises to resolve the following specific aims 1) determine the developmental significance of H3 and H3.3 bimodal incorporation during early embryogenesis and gametogenesis, 2) characterize the genome-wide localization of H3, H3.3, and their post-translational modifications during early embryogenesis, as well as their influence on chromatin accessibility and gene expression and 3) delineate the molecular pathways that orchestrate the developmental regulation of two distinct classes of histone genes important for fertility and cell fate restriction. The completion of this training will develop my research expertise, while delineating the mechanisms underlying the epigenetic regulation of embryonic plasticity, which will be applicable to the fields of reproductive biology, embryology, cellular reprogramming, and fertility.

项目摘要/摘要：早期胚胎细胞具有多能，具有瞬态能力 产生生物体的所有细胞。发育生物学中的一个基本问题确定 临时发展可塑性的基础的表观遗传因素以及了解如何 实现和维护对特定细胞谱系的承诺。如何建立胚胎多能力， 发展是否协调细胞可塑性与细胞命运的获取的限制是 理解不佳。表观遗传现象是指基因表达和染色质组织的变化 通过细胞分裂遗传而不改变潜在的DNA序列。最近，我的研究期间 博士后研究发现了对关键的纳入的未引起的发展调节 表观遗传信息的分子载体，复制偶联组蛋白H3和组蛋白变体H3.3， 在影响早期胚胎的表观遗传组织的配子发生期间，对 多能和血统承诺。 该途径通往独立奖励提案的目的是要求培训支持，以便 在解决表观遗传调节的作用的同时，发展和应用基因组方法的专业知识 早期胚胎发育期间的可塑性以及细胞命运维持。在此期间K99/R00支持 我职业生涯的阶段将成为我作为独立研究人员成功发展的变革。这 该提案中概述的研究计划和职业发展将利用广泛的优势 约翰·霍普金斯大学的资源，以及与基因组学领先专家和 生物信息学。该建议将检查早期的表观遗传调节和发育时机 胚胎可塑性。具体而言，在K99的指导阶段，首席研究员（PI） 将结合当前在约翰·霍普金斯（Johns Hopkins）博士后培训期间产生的专业知识和初步结果 大学，新开发的技术在合作者的实验室中开发了 有关胚胎可塑性和细胞的动态表观遗传机制的基本问题 命运限制。这种方法有望解决以下特定目的1）确定发展 早期胚胎发生和配子发生过程中H3和H3.3双峰掺入的意义，2） 表征H3，H3.3的全基因组定位及其在早期的翻译后修饰 胚胎发生及其对染色质访问性和基因表达的影响，3）描绘 策划了两种不同类型组蛋白基因的发育调节的分子途径 对于生育和细胞命运限制重要。这项培训的完成将发展我的研究专业知识， 同时描述了胚胎可塑性表观遗传调节的基础机制，这将是 适用于生殖生物学，胚胎学，细胞重编程和生育能力领域。