氨基酸修饰组蛋白的机理与作用

Amino acids are the most abundant macromolecules in cells, the building blocks for proteins and one of the three major nutrients utilized by cells. Amino acids are also known as regulators of cellular signaling and physiology. For example, leucyl-tRNA synthetase (LRS) senses intracellular leucine concentration and activates mTORC1; upon binding of glutamine, glutaminyl-tRNA synthetase (QRS) suppresses the proapoptotic activity of apoptosis signal-regulating kinase 1 (ASK1) that facilitates tumorigenesis; tryptophan regulates P53 signaling and DNA damage repairing will be explored. But how amino acids are sensed intracellularly is not fully understood. The applicant found that all 20 proteogenic amino acids can modify ε-amine of lysine and form aminoacylations (Cell Metabolism, 2018). This work provided a new mechanisim of amino acids signals sensed and transmitted. Histone post-translational modifications regulate chromatin-templated processes and play a crucial role in diverse biological processes. Many types of PTMs have been reported at amino acid residues on histones, including histone methylation, acetylation, propionylation. Histone PTMs responsing to metabolism is important for nutrient sensing and environment adaption. The applicant found several types of aminoacylations at over 30 different lysine residues on histones. In the current project, we will confirm function of histone aminoacylations in diverse biological processes, such as cell differentiation and tumor development, by performing experiments in vitro, in culture cells and human samples.

氨基酸不仅是蛋白质合成的基础物质，也是细胞营养的主要来源。我们最新发现，胞内氨基酸可以形成蛋白质氨基酰化修饰，以此传导氨基酸信号并调控多种细胞功能（Cell Metab. 2018）。值得关注的是，我们发现氨基酰化也发生在组蛋白的多个赖氨酸位点，提示氨基酰化是组蛋白结构功能的调控因素。本项目将通过修饰蛋白质组学和生物化学手段确定组蛋白氨基酰化修饰位点和种类；针对前期基本确定的组蛋白谷氨酰胺化修饰，用分子生物学等手段明确其修饰酶和去修饰酶，以及其对谷氨酰胺信号的响应；用细胞生物学和生物化学手段考察谷氨酰胺化对组蛋白和核小体结构的影响；进而用转录组学阐明组蛋白谷氨酰胺化对于下游基因转录的调控作用，重点关注谷氨酰胺化对细胞凋亡、免疫应答、表观遗传等已知谷氨酰胺调控的重要生物学过程相关基因表达的调控。项目的实施将初步阐明氨基酸信号通过转录调控参与细胞功能的分子机制，有助于阐释氨基酸失调的病理意义。

氨基酸不仅是蛋白质合成的基础物质，也是细胞营养的主要来源。我们最新发现，胞内氨基酸可以形成蛋白质氨基酰化修饰，以此传导氨基酸信号并调控多种细胞功能（Cell Metab. 2018）。值得关注的是，我们发现氨基酰化也发生在组蛋白的多个赖氨酸位点，提示氨基酰化是组蛋白结构功能的调控因素。本项目通过修饰蛋白质组学和生物化学手段确定组蛋白氨基酰化修饰位点和种类；针对前期基本确定的组蛋白谷氨酰胺化修饰，用分子生物学等手段明确其修饰酶和去修饰酶，以及其对谷氨酰胺信号的响应；用细胞生物学和生物化学手段考察谷氨酰胺化对组蛋白和核小体结构的影响；进而用转录组学阐明组蛋白谷氨酰胺化对于下游基因转录的调控作用，重点关注谷氨酰胺化对细胞凋亡、免疫应答、表观遗传等已知谷氨酰胺调控的重要生物学过程相关基因表达的调控。本项目不仅探索了氨基酸信号调控细胞周期过程中表观遗传、细胞信号通路等生物学过程，并深入阐释了氨基酸信号失调致肿瘤等疾病发生的分子机制，为相关疾病治疗提供了全新的视角。