SnoRNA分子调控小鼠造血干细胞衰老作用及机制研究

With China moving towards an aging society, researches on aging and related diseases are becoming an urgent issue. Currently, understanding the roles of epigenetic regulators in HSC aging, especially the small nucleolar RNAs (snoRNA) of 50~250 nt in length, are still needed. Our preliminary work demonstrated that number of HSCs decreases and telomere length shortens in aged mice, and gene expression levels of telomere maintenance signaling pathways are significantly reduced. Previous studies have shown that box H/ACA snoRNAs could regulate the length and functionality of telomeres by targeting telomerase RNA component (TERC). Exploiting high through-put small non-coding RNA sequencing technology, we identified snoRNAs which are specifically expressed in aged HSCs. In this study, by use of advanced technologies including pseudouridylation profiling and genetically knockout mice, we will explore the roles and underlying mechanisms how box H/ACA snoRNAs regulate HSC aging by modifying pseudouridylation in TERC. Our work will demonstrate the roles and underlying epigenetic mechanisms of snoRNAs in HSC aging, and provide new insights into the regulation of HSC aging and aging-related diseases.

随着中国人口老龄化趋势逐渐明显，衰老及相关疾病相关机制研究日趋迫切。目前关于表观遗传学因子，特别是长度约50-250nt的核仁小RNA（snoRNA）分子，对HSC衰老的精密调控作用与机制仍缺乏深入的研究。本研究组前期工作发现衰老小鼠中HSC数目增加、端粒变短，衰老HSC中端粒维持信号通路基因显著下调。之前文献报道，H/ACA类型snoRNA分子通过靶向端粒酶复合物中RNA成员TERC来影响端粒长度与功能，进而通过小片段非编码RNA测序鉴定出衰老HSC中snoRNA分子的特异表达谱。本课题拟通过假尿苷酸测序等技术和snoRNA基因敲除小鼠，探索snoRNA分子通过影响端粒酶RNA假尿苷酸化修饰调控HSC衰老的分子机制。本研究对于揭示snoRNA分子调控HSC衰老的作用及详细机制具有重要意义，为理解HSC衰老及相关疾病机制提供新的视角和理论基础。

随着中国人口老龄化趋势逐渐明显，衰老及相关疾病相关机制研究日趋迫切。目前关于表观遗传学因子，特别是长度约50-250nt的核仁小RNA（snoRNA）分子，对HSC衰老的精密调控作用与机制仍缺乏深入的研究。本研究组前期工作发现衰老小鼠中HSC数目增加、端粒变短，衰老HSC中端粒维持信号通路基因显著下调。之前文献报道，H/ACA类型snoRNA分子通过靶向端粒酶复合物中RNA成员TERC来影响端粒长度与功能，进而通过小片段非编码RNA测序鉴定出衰老HSC中snoRNA分子的特异表达谱。在本项目中，我们筛选和鉴定出年轻和衰老小鼠HSC中特征性snoRNA表达图谱，明确小鼠HSC衰老过程中关键snoRNA分子对造血干细胞的多能分化、细胞增殖、凋亡和异种移植功能的作用，并初步阐明snoRNA分子通过影响端粒酶RNA假尿苷酸化修饰调控HSC衰老的分子机制。同时，我们还鉴定出骨髓增生异常综合征患者snoRNA特征性表达图谱，确定SNORA24表达与临床病理指标相关性。本研究对于揭示snoRNA分子调控HSC衰老的作用及详细机制具有重要意义，为理解HSC衰老及相关疾病机制提供新的视角和理论基础。此外，在项目执行期间，共计发表SCI论文9篇，获得国家自然科学基金优青项目1项和国家发明型专利授权2项，参加国际学术会议及国内学术会议各一次，培养博士后3名、博士毕业生1名、硕士毕业生2名，圆满完成项目申请书中的各项预期指标。