Epidermal Gene Regulation by Transcription Elongation and Termination

通过转录延伸和终止调节表皮基因

基本信息

批准号：
10261355
负责人：
Xiaomin Bao
金额：
$ 34.15万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261355
关键词：
Basal cell carcinoma Binding C-terminal CRISPR interference Candidate Disease Gene Cells ChIP-seq Chimeric Proteins Cleavage And Polyadenylation Specificity Factor Cleaved cell Co-Immunoprecipitations Complex Coupled DNA Polymerase II Data Set Development Differentiated Gene Differentiation and Growth Disease Epidermis Epithelial Equilibrium Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomic Segment Genomics Global Change Goals Homeostasis Human Impairment Individual Knowledge Maintenance Malignant Neoplasms Mass Spectrum Analysis Monitor Natural regeneration Pathogenesis Pattern Phosphorylation Play Poly A Polyadenylation Positive Transcriptional Elongation Factor B Process Proteins Proteomics Psoriasis RNA RNA Interference Regulator Genes Research Role Serine Signal Transduction Site Squamous cell carcinoma Testing Tissue Differentiation Tissue Model Tissues Transcription Elongation Transcription Initiation Transcription Repressor Transcriptional Elongation Factors Undifferentiated Work chronic wound design differential expression dosage epidermal stem cell gene function gene product human disease human tissue inhibitor/antagonist insight keratinocyte keratinocyte differentiation knock-down novel novel therapeutics premature recruit scaffold skin disorder tissue regeneration transcription termination transcriptome sequencing wound healing

项目摘要

Project Summary The long-term goal of this project is to elucidate the fundamental gene regulatory mechanisms controlling epidermal tissue homeostasis. Thousands of genes are differentially expressed between undifferentiated and differentiated keratinocytes, yet our current understanding of the gene regulatory mechanisms still remain incomplete. In the context of transcription, which is the first and crucial stage of gene expression, a lot of efforts have been concentrated on the first transcription initiation step. The roles of two other transcription steps, namely the elongation and termination steps, remain largely unexplored. Therefore, this research plan is designed to bridge this knowledge gap by characterizing the regulatory roles of transcription elongation and termination processes in controlling epidermal gene expression. Our preliminary characterization revealed that undifferentiated and differentiated keratinocytes acquire differential expression patterns of transcription elongation and termination regulators. Leveraging our expertise on genomics, proteomics, and human tissue models, we will determine how transcription elongation and termination regulators cooperate with their interacting proteins to differentially regulate the elongation and termination processes to control epidermal progenitor maintenance versus terminal tissue differentiation. Dysregulation of epidermal gene expression underlies the pathogenesis of a spectrum of human skin diseases including psoriasis, chronic wound healing, and cancer. Increased understanding of gene regulation controlled by these under-characterized elongation and termination processes can generate novel therapeutic ideas for treating human skin diseases.

项目概要该项目的长期目标是阐明控制基因的基本调控机制表皮组织稳态。数以千计的基因在未分化和未分化之间差异表达分化的角质形成细胞，但我们目前对基因调控机制的理解仍然存在不完整。在转录的背景下，这是基因表达的第一个也是关键的阶段，需要付出很多努力重点关注第一个转录起始步骤。另外两个转录步骤的作用，即延伸和终止步骤，很大程度上仍未被探索。因此，本研究计划是旨在通过表征转录延伸的调节作用来弥合这一知识差距控制表皮基因表达的终止过程。我们的初步表征表明，未分化和分化的角质形成细胞获得转录延伸和终止调节因子的差异表达模式。利用我们的专业知识在基因组学、蛋白质组学和人体组织模型上，我们将确定转录延伸和终止调节因子与其相互作用的蛋白质合作，差异性地调节伸长和控制表皮祖细胞维持与终末组织分化的终止过程。表皮基因表达失调是一系列人类皮肤发病机制的基础疾病包括牛皮癣、慢性伤口愈合和癌症。增加对基因调控的了解由这些未充分表征的延伸和终止过程控制可以产生新的治疗方法治疗人类皮肤病的想法。