The genetic and epigenetic mechanisms of phenotypic innovationhttps://apps.era.nih.gov/gm/reportCheckList.do?applicationID=9798249

表型创新的遗传和表观遗传机制https://apps.era.nih.gov/gm/reportCheckList.do?applicationID=9798249

• 批准号: 10002266
• 负责人: Li Zhao
• 金额: $ 42.37万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002266
• 关键词: Affinity; Automobile Driving; Binding; Cells; Chromatin; Complex; Data; Development; Drosophila genus; Enhancers; Epigenetic Process; Evolution; Fluorescent in Situ Hybridization; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Health; Human; Life; Link; Modeling; Modification; Molecular Genetics; Morphology; Organ; Phenotype; Process; RNA; Recurrence; Research; Research Proposals; Structure; Testing; Testis; Time; Tissues; XCL1 gene; cell type; disorder risk; innovation; insight; novel; programs; single cell sequencing; single-cell RNA sequencing; theories; trait; transcription factor; whole genome

PROJECT SUMMARY The goal of this research proposal is to dissect the novel regulatory circuits and genes underlying novel traits, to get a better understanding of the genetic basis of morphological and cellular innovation. Every morphological structure or trait originated at some time point in the past and evolved under various evolutionary paths. However, it is unknown how a novel trait originates and how gene and regulatory networks spatially orchestrate the development of the novel cell types, tissues, and organs. Identifying the processes driving and governing morphological and functional diversity and complexity is a major step towards understanding the evolution of complex life. However, our understanding of this process is still limited. The long-term goal of this research program is to functionally characterize the molecular genetic basis of novel cell clusters and novel morphological phenotypes. The central hypothesis is that evolutionary innovations emerging from novel regulatory networks depend on changes in transcription factors and enhancers. Guided by preliminary data including single cell RNA sequencing and well-established theories, the proposed research will test the central hypothesis using an integrative approach. We will determine: 1) regulatory network innovation in novel cell clusters in Drosophila, 2) enhancers responsible for transcription factor expression changes and downstream expression network modification, and 3) the genetic regulatory basis of a novel trait. We performed single-cell sequencing and RNA fluorescent in situ hybridization (FISH) on testis and found a novel cell cluster differentiated between Drosophila species. Combined with ATAC-sequencing data, we will use modeling and functional studies to study the genetic basis of the novel cell cluster. Following this hypothesis that novel enhancers of transcription factors (TFs) are essential for novel traits, we will study the cause of a recurrent novel trait and test the hypothesis that a novel regulatory circuit is essential for a novel trait. We hypothesize that novel enhancers or cis-regulatory motifs of TFs are essential for whole-genome level changes in chromatin accessibility. To test it, we will identify enhancer and motif changes between closely related species to provide insights into enhancer and TF binding affinity co- evolution. This study will provide important insights into the evolution of transcription regulatory networks and their contributions to novel morphological and cellular traits. Altogether, our integrative approach will help to elucidate the origination and evolution of novel regulatory circuits and their contributions to phenotypic innovation.

项目摘要 这项研究计划的目标是剖析新的调控回路和新特征背后的基因， 更好地了解形态和细胞创新的遗传基础。每一种形态 结构或性状起源于过去的某个时间点，并在不同的进化路径下进化。然而，在这方面， 目前尚不清楚一种新的性状是如何起源的，以及基因和调控网络是如何在空间上协调这种新性状的。 新的细胞类型、组织和器官的发展。确定驱动和管理的流程 形态和功能的多样性和复杂性是理解进化的重要一步。 复杂的生命然而，我们对这一过程的了解仍然有限。这项研究的长期目标是 该计划是功能性表征新的细胞簇和新的形态学的分子遗传基础， 表型核心假设是，从新的监管网络中出现的进化创新 依赖于转录因子和增强子的变化。由包括单细胞RNA在内的初步数据指导 测序和完善的理论，拟议的研究将测试中心假设使用 综合办法。我们将确定：1）果蝇新型细胞簇的调节网络创新，2） 负责转录因子表达变化和下游表达网络的增强子 修饰，和3）新性状的遗传调控基础。我们进行了单细胞测序和RNA 利用荧光原位杂交技术（FISH）在果蝇睾丸中发现了一个新的分化细胞簇 物种结合ATAC测序数据，我们将使用建模和功能研究来研究基因的遗传特性。 新型细胞簇的基础。根据这一假设，新的转录因子（TF）增强子是 我们将研究一个反复出现的新特征的原因，并检验一个新特征 调节回路对于一个新的性状是必不可少的。我们假设，新的增强子或顺式调控基序， 转录因子对于染色质可及性的全基因组水平变化至关重要。为了测试它，我们将识别增强剂 和基序的变化密切相关的物种，以提供深入了解增强子和TF结合亲和力共同 进化这项研究将为转录调控网络的进化提供重要的见解， 它们对新的形态学和细胞特征的贡献。总之，我们的综合方法将有助于 阐明新的调节回路的起源和进化及其对表型的贡献 创新