Characterizing functional translation in putative 'noncoding' regions of a genome

摘要 了解基因组是如何对功能信息进行编码的是非常重要的。刻画 这些功能元件可以为生物过程带来新的机械洞察力，从正常的 从发展到疾病进展。我开发了一种计算算法来分析核糖体图谱数据， 并出人意料地揭示了数以千计的短开放阅读框架(SORF)，这些短开放阅读框架(SORF)由假定的“非编码”编码 区域，包括LncRNA、伪基因和5‘UTRs。一些sORF在物种之间是保守的， 暗示了生物学上的重要性。我的结果与其他几个模式物种的遗传研究一起， 为研究基因组中编码的sORF的生物学作用开辟了一个研究前沿。在此，我建议 使用集成的计算和实验基因组学方法系统地表征生物 SORF的功能。首先，我们将研究驱动sORF保守和表达的基本原则 真核生物。其次，我们将研究sORF编码的微肽的稳定性和降解途径。第三, 我们将研究sORF对调节细胞增殖的重要性。最后，我们将研究泛函 SORF翻译在调节RNA稳定性中的作用。综上所述，我们的研究将有助于揭示 对基因组中新发现的翻译区域的表征，并提供了对 RNA翻译和基因组进化之间的相互作用。我们的发现将对 翻译控制和多肽功能在发育和疾病中的分子理解。

ABSTRACT It is fundamentally important to understand how functional information is encoded by a genome. Characterizing these functional elements can bring novel mechanistic insights into biological processes ranging from normal development to disease progression. I developed a computational algorithm to analyze ribosome profiling data, and unexpectedly revealed thousands of short open reading frames (sORFs) encoded by putative ‘noncoding’ regions, including lncRNAs, pseudogenes, and 5’UTRs. Some of the sORFs are conserved across species, suggesting biological importance. My results together with several other genetic studies in model species have opened up a research frontier to study the biological roles of sORFs encoded in a genome. Here I propose to use integrated computational and experimental genomics approaches to systematically characterize biological functions of sORFs. First, we will study basic principles driving sORF conservation and expression across eukaryotes. Second, we will study the stability and degradation pathways of sORF-encoded micropeptides. Third, we will examine the importance of sORFs for regulating cell proliferation. Finally, we will study the functional roles of sORF translation in regulating RNA stability. Taken together, our study will shed light on the functional characterization of the newly identified translated regions in a genome and provide novel insights into the interplay between RNA translation and genome evolution. Our findings will have far-reaching implications for the molecular understanding of translational control and peptide functions underlying development and diseases.