Post-transcriptional regulation of cell plasticity

总结 细胞可塑性是细胞改变其表型的能力，而不会发生基因突变，以响应 环境线索这种细胞行为对于复杂疾病的发展和进展至关重要， 比如免疫反应和癌症细胞转录程序的变化一直被认为是 在细胞类型转换期间确定细胞命运的主要因素。然而，转录后的作用 机制可以在调节细胞命运中发挥作用，特别是在响应环境线索的快速变化时， 是一个黑匣子。我的实验室的一个长期目标是确定调节 蛋白质合成，并了解它们对细胞可塑性的贡献。在这里，我们重点关注两个领域的后- 转录基因调控：mRNA修饰和翻译控制。虽然有令人印象深刻的 在理解RNA修饰和翻译调控在控制细胞凋亡中的作用方面取得了进展。 然而，尽管我们对这些过程如何快速影响细胞内稳态的认识存在很大差距， 可塑性对环境线索变化的反应。真核起始因子3（eIF 3） 通过促进或抑制mRNA的一个子集的翻译，作为翻译调节的主要参与者。 然而，这个关键的起始因子如何控制细胞的可塑性是一个谜。我们的数据表明，eIF 3是关键的 对酵母菌白色念珠菌的形态转变很重要。在主题1中，我们将讨论eIF 3的作用 在控制C.通过回答两个关键问题：1）什么是组成和 eIF 3在不同类型的C.白色念珠菌2）C.白念珠菌eIF 3在调节 酵母菌到菌丝转化过程中的mRNA翻译？我们的第二个研究领域（主题2）的重点是 了解RNA修饰如何调节C.白色念珠菌我们的工作表明， 在C.白念珠菌，抑制mRNA甲基化损害 细胞的可塑性。通过结合我们最近开发的新型遗传工具和试剂 通过生物化学分析、蛋白质组学和下一代测序，我们将回答两个关键问题： 在C.白色念珠菌（4）如何 m6 A mRNA修饰有助于C.白色念珠菌我们的发现将提供重要的 在mRNA或翻译水平上对细胞可塑性的转录后控制机制的见解， 将有助于理解这些过程的失调如何导致人类疾病。

SUMMARY Cell plasticity is the ability of cells to change their phenotypes without genetic mutations in response to environmental cues. This cellular behavior is crucial for the development and progress of complex diseases, such as immune responses and cancer. Changes in cellular transcription programs have long been considered a major factor in defining the fate of cells during cell-type switching. However, the role that post-transcriptional mechanisms can play in regulating cell fate, specifically in response to rapid changes in the environmental cues, is a black box. A long-term goal of my laboratory is to identify the post-transcriptional mechanisms that regulate protein synthesis and understand their contribution to cellular plasticity. Here, we focus on two areas of post- transcriptional gene regulation: mRNA modifications and translational control. While there has been impressive progress towards understanding the role of RNA modifications and translational regulation in controlling cellular homeostasis, there is a significant gap in our knowledge of how these processes can rapidly affect cellular plasticity in response to the changes in environmental cues. The eukaryotic initiation factor 3 (eIF3) has emerged as a master player in translation regulation by promoting or suppressing the translation of a subset of mRNAs. However, how this key initiation factor controls cell plasticity is a mystery. Our data indicate that eIF3 is critically important for morphological transition in the yeast Candida albicans. In Theme 1, we will address the role of eIF3 in controlling cell plasticity in C. albicans by answering two key questions: 1) What are the composition and the interactome of eIF3 in different cell types of C. albicans? and 2) What is the role of C. albicans eIF3 in regulating mRNA translation during the yeast-to-hyphae transition? Our second area of research (Theme 2) is focused on understanding how RNA modifications regulate cell plasticity in C. albicans. Our work demonstrates that mRNAs are differentially methylated in different cell types in C. albicans, and inhibiting the mRNA methylation impairs cell plasticity in this organism. By combining novel genetic tools and reagents that we have recently developed with biochemical assays, proteomics, and next-generation sequencing we will answer two key questions: 3) What is the mechanism of m6A deposition in mRNA during cell-type switching in C. albicans? and 4) How do m6A mRNA modifications contribute to cell-type switching in C. albicans? Our findings will provide significant insights into the mechanisms of post-transcriptional control of cell plasticity at the mRNA or translation level and will aid in understanding how dysregulation of these processes contributes to human disease.