Evolution of gene regulatory networks controlling post-embryonic morphogenesis

控制胚胎后形态发生的基因调控网络的进化

• 批准号: 9911548
• 负责人: Alyssa Woronik
• 金额: $ 1.71万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2020-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911548
• 关键词: Address; Adult; Animal Model; Architecture; Automobile Driving; Bioinformatics; Biological Models; Biological Process; CRISPR/Cas technology; Caenorhabditis elegans; Candidate Disease Gene; Cell physiology; Cells; Congenital Abnormality; Cytology; Data; Development; Developmental Biology; Developmental Process; Education; Educational process of instructing; Educational workshop; Embryo; Embryonic Development; Event; Evolution; Exhibits; Expression Profiling; Faculty; Foundations; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Homologous Gene; Human; Individual; Information Systems; Institution; Knock-out; Knowledge; Learning; Light; Maps; Mentors; Modeling; Morphogenesis; Morphology; Mutation; Natural regeneration; Nematoda; Neoplasm Metastasis; New York; Organism; Outcome; Pharmaceutical Preparations; Phylogenetic Analysis; Play; Positioning Attribute; Process; Proxy; Regulator Genes; Research; Research Personnel; Resources; Role; Series; Tail; Techniques; Testing; Time; Tissues; Training; Universities; Validation; Work; base; career; developmental genetics; epigenetic regulation; experience; in vivo; insight; interest; knock-down; male; network architecture; notch protein; novel; prevent; protein biomarkers; sex; skills; spatiotemporal; symposium; theories; tool; transcription factor; transcriptome sequencing; undergraduate student; wound healing

Evolution of gene regulatory networks controlling post-embryonic morphogenesis Morphogenesis, or the development of form, is a universal process during development of multicellular organisms that is controlled by the precise spatiotemporal expression of genes within gene regulatory networks (GRNs). While advances have been made in elucidating GRNs that control embryonic development in model organisms, we lack an understanding of how GRNs regulate post-embryonic morphogenesis and how these networks evolve. The hotspot hypothesis predicts that the architecture of GRNs can bias evolution, such that morphologies evolve via repeated co-option of a master regulator (i.e. a gene that is required and sufficient for morphogenesis). This proposal will use a post-embryonic morphogenic process, known as Tail Tip Morphogenesis (TTM), which evolved multiple times independently in Caenorhabditis elegans and related species, to investigate the architecture and evolution of GRNs, and test the hotspot hypothesis. In C. elegans, DMD-3, a DM-domain transcription factor, is the master regulator within the GRN governing TTM. Aim 1 uses single-tissue RNA-Seq in a time series over the course of TTM in lineages where TTM independently evolved. Then computationally infer the GRN underlying TTM in each species. The inferred GRNs will be used to test the hotspot hypothesis and will contribute to our general understanding of how GRNs drive morphogenesis and how plastic GRN architectures can be. Aim 2.1 validates the hotspot hypothesis by knocking out dmd-3, or another candidate regulator inferred from Aim 1, in species where TTM independently evolved. Aim 2.2 validates the predicted downstream interactions within the GRN by using single-tissue RNA-Seq on the regulator knockout lines. Aim 3 investigates the functional role of conserved modules (i.e. sets of genes and their interactions) within the GRNs that have human homologs. As DMD-3 is a homolog to DMRT-1, required for male fates in humans, regulators and effectors of DMD-3 could be candidate targets for future drugs or therapies that could, for example, help people with sex reversal. Additionally, because morphogenesis is a universal developmental process, this work will also likely identify genes that are conserved in other morphogenic processes, such as cancer metastasis, regeneration, and wound healing. This project will be conducted within the Center for Developmental Genetics at New York University, a world- renowned research institution with top-notch resources and faculty, under the advisement of Prof. David Fitch who has 25 years of experience as a researcher, mentor, and educator in the field of evolutionary developmental biology. My training goals are to 1) expand my knowledge in developmental biology, 2) learn developmental genetics wet lab techniques, 3) continue my education in bioinformatics, 4) develop teaching and mentoring skills, 5) develop species related to C. elegans into satellite model systems to use in my independent research career. These goals will be achieved using the above research as a platform in addition to mentoring from Prof. Fitch, workshops, conferences, and mentoring undergraduates.

控制胚胎后形态发生的基因调控网络的进化 形态发生，或形式的发展，是多细胞发育过程中的普遍过程 受基因调控网络内基因精确时空表达控制的生物体 （GRN）。虽然在阐明模型中控制胚胎发育的 GRN 方面已经取得了进展 对于生物体，我们缺乏对GRNs如何调节胚胎后形态发生以及它们如何调节的了解。 网络不断发展。热点假说预测 GRN 的架构可能会导致进化出现偏差，例如 形态通过主调节器的重复选择而进化（即，需要且足以实现 形态发生）。该提案将使用胚胎后形态发生过程，称为尾尖 形态发生（TTM），在秀丽隐杆线虫和相关物种中独立进化了多次 种，研究 GRN 的结构和进化，并检验热点假设。在秀丽隐杆线虫中， DMD-3 是一种 DM 结构域转录因子，是 GRN 内控制 TTM 的主要调节因子。目标 1 使用 在 TTM 独立进化的谱系中，对 TTM 过程中的时间序列进行单组织 RNA 测序。 然后通过计算推断每个物种中 TTM 的 GRN。推断的 GRN 将用于测试 热点假说，将有助于我们对 GRN 如何驱动形态发生和 GRN 架构的可塑性如何。目标 2.1 通过敲除 dmd-3 验证热点假设，或者 从 Aim 1 推断出的另一个候选调节因子，在 TTM 独立进化的物种中。目标2.2 通过使用单组织 RNA-Seq 验证 GRN 内预测的下游相互作用 调节器淘汰线。目标 3 研究保守模块（即基因组和 它们的相互作用）在具有人类同源物的 GRN 中。由于 DMD-3 是 DMRT-1 的同系物，因此需要 对于人类男性的命运，DMD-3 的调节因子和效应因子可能是未来药物或药物的候选目标 例如，可以帮助性逆转患者的疗法。此外，由于形态发生是 普遍的发育过程中，这项工作也可能会识别其他基因中保守的基因 形态发生过程，例如癌症转移、再生和伤口愈合。 该项目将在纽约大学发育遗传学中心进行，该中心是世界性的 著名研究机构，拥有一流的资源和师资，在 David Fitch 教授的指导下 他在进化论领域拥有 25 年的研究员、导师和教育家经验 发育生物学。我的培训目标是 1) 扩展我在发育生物学方面的知识，2) 学习 发育遗传学湿实验室技术，3）继续我的生物信息学教育，4）发展教学 和指导技能，5）将与秀丽隐杆线虫相关的物种开发成卫星模型系统，以便在我的研究中使用 独立的研究生涯。此外，这些目标将利用上述研究作为平台来实现 菲奇教授的指导、研讨会、会议以及指导本科生。