Functional analysis of regulated mRNA 3'end processing in the control of inflammatory processes, innate immunity and tumorigenesis

控制基因表达的转录后机制在健康和疾病中发挥着越来越多的作用1 -6。虽然已经取得了实质性的进展，许多这些机制的特点，mRNA的3 '端加工的调控仍然知之甚少。重要的是，替代和调节mRNA 3 '末端加工调节许多基因的表达7，8，通常响应于细胞外刺激6，8-10。尽管有这些发现，但涉及的信号转导途径及其在执行特定细胞程序中的作用尚不清楚。我将整合生物信息学，生物化学和功能基因组学的方法来剖析调控mRNA 3 '端加工的分子和细胞机制。我们将确定功能相关的因素和信号通路，调节这一步的mRNA加工响应外部刺激。此外，我们将探讨是否一类新的转录本，其中3 '端加工被激活的特定序列elements 6，11-19，代表一个功能耦合的RNA操纵子，以执行细胞程序响应外部刺激20，21。有趣的是，这一类包括许多在炎症和肿瘤发生中起关键作用的转录本。这些发现将被转化为疾病模型，最终可以为治疗干预提供体内验证的靶点和/或信号成分的新见解。

Posttranscriptional mechanisms that control gene expression play an increasingly recognized role in health and disease1-6. While substantial progress has been made to characterize many of these mechanisms, the regulation of mRNA 3’end processing is still poorly understood. Importantly, alternative and regulated mRNA 3’end processing modulates the expression of many genes7,8, often in response to extracellular stimuli6,8-10. Despite these findings, the involved signal-transduction pathways and their role to execute specific cellular programs are unknown. I will integrate bioinformatical, biochemical and functional genomic approaches to dissect the molecular and cellular mechanisms of regulated mRNA 3’end processing. We will identify functionally relevant factors and signaling pathways that modulate this step of mRNA processing in response to external stimuli. Furthermore, we will explore whether a novel class of transcripts, in which 3’end processing is activated by specific sequence elements6,11-19, represents a functionally coupled RNA operon to execute cellular programs in response to external stimuli20,21. Interestingly, this class includes many transcripts with key roles in inflammation and tumorigenesis. These findings will be translated into disease models that could ultimately provide novel insights into in vivo-validated targets and/or signaling components for therapeutic intervention.