长非编码RNA编码的微肽在p53信号通路中的功能和机制研究

Long non-coding RNAs (lncRNAs) encoded micropeptides are a new class of regulatory molecules and involve in the regulation of diverse physiological and pathological processes. However, the expression and functional importance of these micropeptides in cellular signaling pathway remain to be elucidated, including the p53 pathway. In our previous studies, the transcriptome and translatome analyses in hepatoma carcinoma cells upon p53 activation showed that a batch of new lncRNAs encoded micropeptides were transcriptionally regulated by p53. Therefore, we hypothesize that these micropeptides are important new members of the p53 signaling pathway and play critical roles in regulating various cellular biological processes by synergizing with p53. We thus set out to systematically explore micropeptides encoded by p53-regulated lncRNAs in p53 signaling pathway based on integrative approach of experiments and next-generation sequencing, including RNA-seq, Ribo-seq and ChIP-seq. Moreover, we will investigate the expression and transcriptional regulation of micropeptides that are directly controlled by p53, as well as the function of those p53-regulated micropeptides involved in DNA damage repair, tumorigenesis and progression. Altogether, the study will expand our understanding on the mechanism of coordinated regulation between micropeptides and the p53 signaling pathway, and provide new potential targets for tumors and other diseases.

长非编码RNA（lncRNA）编码的微肽（micropeptide）是一类新的调控分子，参与各种生物体生理和病理过程的调控。然而，这些微肽在细胞重要信号通路（如p53通路等）中的表达调控及功能机制尚不清楚。我们前期在激活p53的肝癌细胞模型中进行的转录组和翻译组分析发现，p53转录调控了一批新的由长非编码RNA编码的微肽。由此我们推测，长非编码RNA编码的微肽是p53信号通路的重要新成员，并协同p53在细胞生命活动中发挥重要的调控作用。在此基础上，本项目拟结合实验方法和RNA-seq、Ribo-seq和ChIP-seq等高通量测序手段，系统鉴定肝癌中p53调控的长非编码RNA及其编码的微肽，阐明这些微肽表达调控的分子机制，解析p53调控的微肽在DNA损伤修复、肿瘤发生发展等生物学过程中的作用，揭示微肽与p53信号通路之间的协同调控机制，为肿瘤等疾病研究提供新的潜在靶标。

长非编码RNA（lncRNA）编码的微肽（micropeptide）是一类新的调控分子，参与各种生物体生理和病理过程的调控。本项目结合核糖体图谱测序技术（Ribo-seq）、RNA-seq等高通量测序技术和CRISPR/Cas9基因编辑技术，在DNA损伤修复细胞模型中系统鉴定到了300多个受p53调控的lncRNA和200多个具有编码潜能的lncRNA；通过功能缺失及获得实验发现受p53调控的lncRNA编码微肽TP53LC02和TP53LC04能够抑制多种癌细胞的增殖，且发挥作用的是微肽分子而非lncRNA分子；并且发现TP53LC04微肽可以通过调控细胞周期去参与p53介导的肿瘤抑制。该研究揭示了lncRNA编码的微肽在p53调控网络中充当的全新角色，拓展了人们对p53调控网络的认识，并将为癌症有效治疗提供了新的潜在靶点。在大鼠心肌肥大疾病模型中，我们也发现了一批非编码RNA编码的微肽，其可以通过调节氧化磷酸化，钙离子信号通路和MAPK信号通路参与对心肌肥大的调控，这对于更加深入而全面地了解心肌肥大病理过程和寻找潜在的药物靶点具有重要意义。此外，我们从癌基因调控的非编码RNA出发，解析癌基因CREB1对结肠癌细胞可塑性调控的新机制，揭示肿瘤的精准治疗必须靶向癌细胞的可塑性；并开发了基于高通量测序技术与数据的非编码RNA表观修饰鉴定方法和功能分析平台。这些研究极大地拓展了我们对非编码RNA的功能机制的认识。