Epidermal Gene Regulation by Transcription Elongation and Termination

项目摘要 该项目的长期目标是阐明控制基因表达的基本基因调控机制。 表皮组织稳态数千个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， 已经集中在第一转录起始步骤上。另外两个转录步骤的作用， 即延伸和终止步骤，在很大程度上仍未被探索。因此，该研究计划是 旨在通过表征转录延伸的调节作用来弥合这一知识差距， 终止过程控制表皮基因表达。 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 终止调节因子与它们的相互作用蛋白质协同作用，以差异性地调节延伸， 终止过程以控制表皮祖细胞维持相对于终末组织分化。 表皮基因表达失调是一系列人类皮肤病发病机制的基础 包括牛皮癣、慢性伤口愈合和癌症的疾病。增加对基因调控的理解 通过这些未充分表征的延伸和终止过程来控制， 治疗人类皮肤病的想法。

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.