Molecular mechanisms reprogramming transcription in quiescent cells

静止细胞中转录重编程的分子机制

• 批准号: 10895178
• 负责人: Benjamin Roche
• 金额: $ 18.24万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10895178
• 关键词: Molecular; mechanisms; reprogramming; transcription; quiescent

The long-term goal of the proposed research is to characterize the molecular mechanism(s) by which cells are reprogrammed into quiescence. This reprogramming is essential for cells to maintain viability over long periods of time without divisions, such as quiescent stem cells and memory lymphocytes. On the other hand, this reprogramming also allows early-disseminated cancer cells to evade treatment by maintaining their state of quiescence. Therefore, deciphering the mechanisms and factors involved in cellular quiescence is both a fundamental biological question and informative in health and disease. We are approaching this in a systematic manner by focusing on a model organism, the fission yeast S. pombe. This model has a ‘minimal set’ of genes allowing viable long-term quiescence, and retained epigenetic mechanisms such as histone marks and RNA interference, which are essential in non-dividing cells. By identifying this minimal set and using high-throughput approaches available in fission yeast, our goal is to understand the basic principles and key components of reprogramming in quiescence, without the confounding effects due to the added complexity of multicellular organisms, where differentiation and intercellular communication occur and affect quiescence. Among several pathways that we have found to be essential for quiescence maintenance, we are focusing specifically on two complementary factors, which are not only conserved across eukaryotes, but also most likely to impact our understanding of reprogramming: in aim 1, we will study how a core component of the Mediator complex is essential specifically in quiescent cells to maintain basal transcriptional activity; in aim 2, we will focus on ERH, a small enigmatic protein, which acts as a repressor of transcription in quiescence. We will employ a combination of genetic, genomic, biochemistry and bioinformatics approaches to understand how these two complementary regulators shape gene expression in quiescent cells. Because both Mediator and ERH are mis-expressed in cancers with strong metastatic potential, we expect our results to shed some light not only on transcriptional reprogramming in physiological quiescent cells, but also on how this process is mis-regulated in tumor dormancy.

拟议研究的长期目标是表征细胞的分子机制 被重新编程为静止。此重编程对于细胞维持生存能力至关重要 长时间没有分裂的时间，例如静止的干细胞和记忆淋巴细胞。在 另一方面，此重编程还允许早期脱落的癌细胞通过 保持其静止状态。因此，破译所涉及的机制和因素 细胞静止既是一个基本的生物学问题，又是健康和疾病的信息。 我们通过专注于模型生物，裂变酵母S来实现系统的方式。 Pombe。该模型具有“最小”基因，允许长期静止，并保留 表观遗传机制，例如组蛋白标记和RNA干扰，在非分裂中必不可少 细胞。通过识别这种最小的集合并使用裂变酵母中可用的高通量方法，我们 目标是了解静止的重新编程的基本原理和关键组成部分，而没有 由于多细胞生物的复杂性增加，分化和分化和 细胞间通信发生并影响静止。 在我们发现对静止至关重要的几种途径中，我们是 专门针对两个完善因素，这些因素不仅在真核生物之间构成，而且还构成 同样最有可能影响我们对重编程的理解：在AIM 1中，我们将研究核心 介体复合物的组成部分本质上是在静态细胞中的专门 转录活动；在AIM 2中，我们将专注于一种小型神秘蛋白ERH，它充当 静止的转录阻遏物。我们将结合遗传，基因组，生物化学 和生物信息学的方法，以了解这两个完整的调节因子如何塑造基因 静态细胞中的表达。因为调解人和ERH都在强烈的癌症中都误表达了 转移性电位，我们期望我们的结果不仅会在转录重新编程中阐明 生理静止的细胞，以及该过程在肿瘤休眠状态中如何错过。