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 形态发生或形态的发育是多细胞生物发育过程中的一个普遍过程。 受基因调控网络中基因精确时空表达控制的生物体 （GRNs）。虽然在阐明模型中控制胚胎发育的GRNs方面取得了进展， 生物，我们缺乏对GRNs如何调节胚胎后形态发生以及这些调控机制的理解。 网络进化。热点假说预测，GRNs的结构可以使进化发生偏差， 形态通过主调节子（即，对于生物体而言是必需且足够的基因）的重复共选择而进化。 形态发生）。这项建议将使用胚胎后的形态发生过程，称为尾尖 形态发生（TTM），在秀丽隐杆线虫和相关的 物种，研究GRNs的结构和进化，并验证热点假说。In C.优雅， DMD-3是一种DM结构域转录因子，是GRN中控制TTM的主要调节因子。Aim 1使用 在TTM独立进化的谱系中，在TTM过程中的时间序列中的单组织RNA-Seq。 然后通过计算推断每个物种的TTM背后的GRN。推断的GRN将用于测试 热点假说，并将有助于我们对GRNs如何驱动形态发生的一般理解， 塑料GRN架构是什么样的目标2.1通过敲除DMD-3来验证热点假说，或者 从Aim 1中推断出另一个候选调节因子，存在于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， 调节器分离管线。目的3研究保守模块（即基因组和 它们之间的相互作用）。由于DMD-3是DMRT-1的同源物，因此需要 对于人类的男性命运，DMD-3的调节剂和效应物可能是未来药物的候选靶点， 比如说，可以帮助性逆转的人的疗法。此外，由于形态发生是一个 普遍的发展过程，这项工作也可能确定基因是保守的，在其他 形态发生过程，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，该中心是一个世界性的研究中心， 在大卫惠誉教授的指导下，拥有一流资源和师资的著名研究机构 他在进化论领域拥有25年的研究人员、导师和教育工作者的经验， 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 发展遗传学湿实验室技术，3）继续我在生物信息学方面的教育，4）发展教学 5）开发与C.卫星模型系统中使用， 独立的研究生涯。这些目标的实现将以上述研究为平台， 从惠誉教授的指导，研讨会，会议和指导本科生。

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.