High resolution genomic and epigenomic mapping of the human salivary gland

人类唾液腺的高分辨率基因组和表观基因组图谱

• 批准号: 10727190
• 负责人: Rose-Anne Romano
• 金额: $ 44.1万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727190
• 关键词: 3-Dimensional; ATAC-seq; Adult; Aging; Area; Autoimmune Diseases; Biological Models; Biological Process; Biology; Cell Communication; Cells; ChIP-seq; Chemotherapy and/or radiation; Chromatin; Chromium; Communication; Complex; Computer Analysis; Data; Data Set; Digestion; Disease; Ecosystem; Embryo; Endothelium; Enhancers; Epithelium; Experimental Models; Female; Fibroblasts; Follow-Up Studies; Food; Functional disorder; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genome; Genomics; Gland; Goals; Histones; Homeostasis; Human; Immune; Individual; Inflammatory; Investigation; Knowledge; Link; Malignant Neoplasms; Maps; Microbe; Minor salivary gland structure; Molecular; Multiomic Data; Mus; Neurons; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Nucleosomes; Oral cavity; Oral health; Organ; Organism; Parotid Gland; Pathologic; Physiological; Play; Population; Process; Regulation; Regulator Genes; Research; Resolution; Resources; Role; Salivary Gland Diseases; Salivary Glands; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Sjogren' s Syndrome; Sublingual Gland; Submandibular gland; System; Technology; Testing; Therapeutic Intervention; Tissue-Specific Gene Expression; Tissues; Untranslated RNA; Variant; Work; cell type; computerized tools; connectome; epigenome; epigenomics; experimental study; gene regulatory network; genetic variant; genome wide association study; genome-wide analysis; human disease; improved; in vivo; innovation; insight; intercellular communication; knowledge base; male; prevent; progenitor; programs; promoter; saliva secretion; single-cell RNA sequencing; therapeutically effective; tool; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY A mechanistic and molecular examination of the differentiation programs and normal tissue homeostasis of the salivary glands (SG) is an important area of research since altered SG function is associated with multiple human disease conditions including Sjogren syndrome, cancer, and complications due to cancer chemo/radiation therapy. This necessitates an in-depth investigation of the complex ecosystem of SG that consists of a variety of epithelial and non-epithelial cell populations that cooperatively interact to facilitate SG function. The underlying molecular circuitry of the transcriptional and epigenomic gene-regulatory mechanisms that control SG biology, particularly as it pertains to individual cell types in the in vivo context of the human SG, however, is not very well-understood and thus presents a significant knowledge gap. Lack of this knowledge prevents a better understanding of principles of cell fate and lineage choices, cell-to-cell communication and transcriptional regulatory processes that are needed for guiding effective therapeutic interventions of human diseases. Our central hypothesis is that the establishment of the SG transcriptome, epigenome and gene regulatory networks is a dynamic process that results from reciprocal interactions between intracellular signaling pathways and the underlying hardwired genomic information of each cell-type. To test this hypothesis, three specific aims are proposed. Aim 1 is to generate single-cell RNA-sequencing (scRNA-seq), and scATAC-seq data from the same cells of the adult male and female SMG. The goals of Aim 2 are to use computational tools to define the cell fate trajectories and cell-to-cell communication systems that operate in the SG and identify crucial transcriptional regulators that define cell fate. Finally in Aim 3, the 3D chromatin state and the enhancer-promoter connectome map of the human SG will be established by HiChIP experiments. Such data will enable the establishment of the link between non-coding genetic variants and disease-associated genes that are relevant for disease such as Sjogren’s syndrome that primarily afflict the SG. This work is highly innovative and significant because our proposed use of cutting-edge technologies and sophisticated tools to examine fundamental transcriptional and epigenomic mechanisms of gene regulation and signaling pathways at a single cell resolution. Long term, such knowledge will substantially advance the fundamental understanding of SG biology and is anticipated to have a long-term impact on the treatment of complex genetic diseases of the SG.

项目总结 分化程序和正常组织的机制和分子检查 唾液腺的动态平衡是一个重要的研究领域，因为唾液腺功能的改变是 与多种人类疾病相关，包括干燥综合征、癌症和因 癌症化疗/放射治疗。这就需要深入研究地球上的复杂生态系统 SG由多种上皮性和非上皮性细胞群组成，它们协同作用于 促进销售总监的职能。转录和表观基因组基因调控的潜在分子回路 控制SG生物学的机制，特别是当它与活体背景下的单个细胞类型有关时 然而，人类的SG并没有被很好地理解，因此存在着显著的知识鸿沟。缺乏 这种知识阻碍了对细胞命运和谱系选择原则的更好理解，细胞对细胞 指导有效治疗所需的沟通和转录调控过程 人类疾病的干预。我们的中心假设是SG转录组的建立， 表观基因组和基因调控网络是一个相互作用的动态过程 在细胞内信号通路和每种细胞类型的潜在硬连接基因组信息之间。 为了验证这一假设，本文提出了三个具体目标。目标1是产生单细胞RNA测序 (scRNA-seq)，以及来自成年雄性和雌性SMG相同细胞的scATAC-seq数据。AIM的目标 2是使用计算工具来定义细胞命运轨迹和细胞间通信系统 在SG中运作，并确定决定细胞命运的关键转录调控因子。最后在《目标3》中，3D 人SG染色质状态和增强子-启动子连接组图将由HiChIP建立 实验。这类数据将能够在非编码遗传变异和 与干燥综合征等疾病相关的疾病相关基因，这种疾病主要困扰 SG.这项工作具有很高的创新性和重要意义，因为我们建议使用尖端技术和 用于研究基因调控的基本转录和表观基因组机制的复杂工具 以及在单个细胞分辨率下的信号通路。从长远来看，这种知识将大大推动 对脑血管病生物学有基本的了解，并有望对脑血管病的治疗产生长期影响。 SG的复杂遗传病。