Yingming Zhao教授致力于生物分析科学以及蛋白质组学研究, 主要涉及的领域有组蛋白修饰、蛋白质组学等。在高水平杂志上发表论文160多篇，引用超过23000次，H-index: 80。受邀学术报告200余场。担任多个国际学术组织board member，以及Science, Cell, Nature, Molecular Cell, Nature Chemistry Biology, Nature Biotechnology, Nature Communications, Nature Method, Trends in Biochemistry, Trends in Endocrinology & Metabolism, PNAS, Molecular and Cellular Proteomics, J. Proteome Res., Proteomics, Analytical Chemistry, J.A.C.S多个学术期刊的审稿人。
Functional characterization of thousands of small molecules in mammalian cells represents one of the major daunting challenges in biology. The cellular metabolites can activate or inhibit functions of a protein or protein complex, covalently or non-covalently. Decoding of the metabolite – protein networks would better understanding cellular regulation and physiology. In this presentation, we will report our efforts to develop a systematic approach for identifying and validating new protein post-translational modifications (PTMs). We discovered lysine short-chain acylations as new types of epigenetic mechanism and as functional destination for short-chain lipids. We detected and comprehensively validated nine types of new short-chain, lysine acylation pathways: propionylation, butyrylation, crotonylation, malonylation, succinylation, glutarylation, 2-hydroxyisobutyrylation, 3-hydroxybutyrylation, and benzoylation. We identified ~500 histone marks bearing the new PTMs, which almost doubled the number of previously described histone marks that were discovered over the past few decades. We subsequently characterized the new PTM pathways by chemical proteomics and chemical biology approaches, in combination with other biological tools. Using the MS-based proteomics approach, we identified thousands of substrates for these PTM pathways, including acetyllysine and succinyllysine substrates. We and others identified regulatory enzymes that can add or remove lysine acylations. Interestingly, we showed that diverse HATs and HDACs (e.g., SIRT5) have high activities to these new lysine acylations but not lysine acetylation, suggesting that some of HDACs were mistakenly classified as deacetylases. These new PTM pathways are associated with gene expression, cellular physiology and diverse metabolic diseases. Accordingly, our study lays a foundation for studying biological functions of the short-chain metabolites and the PTM pathways, including but not limited to their roles in epigenetics and in disease.