An inquiry into the function of Ronin in embryogenesis and pluripotent stem cells

Ronin在胚胎发生和多能干细胞中的功能探究

基本信息

批准号：
9897561
负责人：
Thomas P. Zwaka
金额：
$ 46.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-11 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897561
关键词：
Apoptosis Binding Binding Sites Cancer Biology Cell Nucleus Cells Chromatin Loop Chromosome Mapping Communication Complex Congenital Abnormality DNA Binding DNA Binding Domain DNA Transposons DNA-Binding Proteins Data Defect Development Developmental Gene Dimerization Disease Distant Elements Embryonic Development Enhancers Event Evolution Family Family member Gene Cluster Gene Expression Gene Expression Regulation Gene Family Genes Genetic Enhancer Element Genetic Transcription Genome Heart Heart Diseases Human In Vitro Link Maintenance Mediating Medicine Molecular Mustard Nematoda Neurologic Nuclear Protein Organelles Phosphorus Pluripotent Stem Cells Process Promoter Regions Proteins Recording of previous events Regulator Genes Reporting Resolution Stem Cell Development Testing Traction Transactivation Transcriptional Regulation Ursidae Family Zinc Fingers cancer type combinatorial embryonic stem cell gene interaction in vivo insight member organ growth pluripotency promoter recruit research study stem cell biology stem cells transcription factor

项目摘要

PROJECT SUMMARY A long-held view is that gene regulatory complexity in stem cells and development is achieved through the judicious organization of millions of enhancer elements. A recently identified new class of DNA binding fac- tors called THAPs (Thanatos-associated domain-containing apoptosis-associated proteins) may provide new insights into gene regulation in stem cells. One key member of this family, Ronin (Thap11), was discovered by us in embryonic stem cells. Ronin is expressed during the earliest stages of embryonic development and is essential for the maintenance of stem cell pluripotency, both in vitro and in vivo. Since Ronin lacks appreciable transac- tivation activity but functions as a DNA-binding nuclear protein with strong protein dimerization activity, we considered that it may not act in the classical manner of a transcriptional regulator (e.g., having an acidic activa- tion domain) but instead might augment gene expression by facilitating communication among Ronin binding sites through DNA looping. This working hypothesis gained traction when we found that most (83%) of the looping events mediated by Ronin involve promoter-to-promoter links rather than the enhancer-to-promoter interactions seen with typical transcription factors. In this research study we will (i) establish the effects of Ro- nin-mediated promoter tethering on transcription and gene regulation in stem cells; (ii) determine the influence of promoter tethering on developmental transitions especially from the naïve to primed pluripotent state; and (iii) ask if other THAPs participate in development specific gene clustering as well.

项目概要长期以来的观点是，干细胞和发育中的基因调控复杂性是通过最近发现的一类新的 DNA 结合因子的明智组织。称为 THAP（Thanatos 相关结构域的细胞凋亡相关蛋白）的蛋白可能提供新的我们发现了该家族的一个关键成员 Ronin (Thap11)，从而深入了解干细胞中的基因调控。 Ronin 在胚胎发育的最早阶段表达，并且是必需的。用于维持干细胞多能性，无论是体外还是体内。激活活性，但作为具有强蛋白质二聚活性的 DNA 结合核蛋白发挥作用，我们认为它可能不会以转录调节因子的经典方式起作用（例如，具有酸性活性化域），但可能通过促进 Ronin 结合之间的通讯来增强基因表达当我们发现大多数（83%） Ronin 介导的循环事件涉及启动子到启动子的连接，而不是增强子到启动子的连接在这项研究中，我们将 (i) 确定 Ro- 的影响。 (ii) 确定影响启动子对发育转变的影响，特别是从幼稚状态到引发多能状态的转变； (iii) 询问其他 THAP 是否也参与发育特异性基因聚类。