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

基本信息

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
项目类别：
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

项目摘要

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：早期胚胎细胞是多能的，具有瞬时能力产生有机体的所有细胞。发育生物学的一个基本问题涉及识别这种暂时的发育可塑性背后的表观遗传因素，以及了解如何实现并维持对特定细胞谱系的承诺。胚胎多能性是如何建立的，发育是否协调细胞可塑性的限制与细胞命运的获得不太了解。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，我在学习期间博士后研究发现了一个未受重视的关键整合的发育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，在配子发生过程中，影响早期胚胎的表观遗传组织，对多能性和血统承诺。此独立之路奖提案的目标是请求培训支持，以便发展基因组方法的专业知识并应用基因组方法，同时解决表观遗传调控的作用早期胚胎发育过程中的可塑性以及细胞命运的维持。在此期间支持K99/R00 我职业生涯的阶段将对我作为独立研究员的成功发展产生变革。这本提案中概述的研究计划和职业发展将利用广泛的约翰·霍普金斯大学的资源，并与基因组学领域的领先专家合作生物信息学。该提案将研究早期的表观遗传调控和发育时间。胚胎的可塑性。具体来说，在该奖项的 K99 指导阶段，首席研究员 (PI) 将结合当前的专业知识和约翰·霍普金斯大学博士后培训期间产生的初步结果大学，利用合作者实验室开发的新技术来回答关于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具体目标 1）确定发展 H3 和 H3.3 双峰掺入在早期胚胎发生和配子发生过程中的重要性，2) 表征 H3、H3.3 的全基因组定位及其早期翻译后修饰胚胎发生，以及它们对染色质可及性和基因表达的影响，3）描绘协调两类不同组蛋白基因发育调控的分子途径对于生育力和细胞命运限制很重要。完成本次培训将发展我的研究专业知识，同时描述胚胎可塑性表观遗传调控的机制，这将是适用于生殖生物学、胚胎学、细胞重编程和生育力等领域。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmentally programmed histone H3 expression regulates cellular plasticity at the parental-to-early embryo transition.

发育程序组蛋白 H3 表达调节亲本到早期胚胎转变的细胞可塑性。

DOI：
发表时间：
2023-04-07
期刊：
影响因子：
13.6
作者：
Gleason, Ryan J;Guo, Yanrui;Semancik, Christopher S;Ow, Cindy;Lakshminarayanan, Gitanjali;Chen, Xin
通讯作者：
Chen, Xin

Epigenetic dynamics during germline development: insights from Drosophila and C. elegans.

种系发育过程中的表观遗传动力学：来自果蝇和线虫的见解。