Xiucong Bao - Study on the Cellular Regulation and Function of Lysine Malonylation, Glutarylation and Crotonylation

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It is a great pleasure to write this foreword for the thesis of Dr. Xiucong Bao. She joined my research group in 2012 and received her Ph.D. degree in 2016. She has made outstanding achievements in her research in the field of chemical biology, as demonstrated by her excellent publications in many top chemistry and biology journals, as well as the numerous regional and international awards she has obtained.

In my laboratory, she has been trying to develop chemistry-based approaches to understand our life processes and to address issues in human health. She is particularly interested in elucidating complex regulatory mechanisms and functions of protein posttranslational modifications (PTMs, e.g., acetylation, methylation, and phosphorylation), the naturally occurring chemical modifications of proteins after their translation from DNA. PTMs regulate essentially every biological process, ranging from DNA replication and gene expression, to cell cycle control, signal transduction, and metabolism. Given these numerous links to essential cellular processes, it is not surprising that improper regulation of PTMs often leads to human diseases such as cancer. Therefore, it is of great importance to understand the roles of PTMs in normal cell biology and disease pathogenesis. However, while more than 300 different types of protein PTMs have been identified, functions of the vast majority of them remain poorly understood. This is particularly the case for those newly identified PTMs.

The thesis work of her covered important aspects of chemical epigenetics. Her first research project focused on a recently identified PTMprotein lysine malonylation. Because of its distinct chemical structure, malonylation was believed to have significant effects on its modified proteins structure and function. However, the lack of knowledge about the cellular substrates of malonylation curbs the enthusiasm of examining the biological significance of this new PTM. To fill this knowledge gap, she decided to take chemical tools and approaches. To be honest, I expected little on the progress by this first-year Ph.D. student who just experienced a transition from an undergraduate student major in biology to a chemistry postgraduate student. However, she indeed very much surprised and impressed me. Taking only six months, she has successfully developed a chemical reporter for rapid detection of malonylated proteins. The use of this chemical reporter allowed us, for the first time, to see malonylation dynamics (i.e., fast processes of addition and removal of the modification) in living human cells. She then took a step forward by combing her chemical reporter with the state-of-the-art mass spectrometry to comprehensively profile malonylated proteins in human proteomes and finally led to the identification of 361 new protein candidates. Her outstanding research work has greatly expanded the substrate inventory of malonylation and paved the way for further study of biological significance of this newly identified PTM. This work finally resulted in an outstanding paper and cover story inAngewandte Chemie, a top chemistry journal, in 2013.

After completing the first project, she has focused on the study of PTMs of histone proteins, around which genomic DNA is wrapped to form chromatin. She got interested in a recently discovered histone PTM, lysine crotonylation (Kcr). Kcr was found to be enriched at active gene promoters and potential enhancers in mammalian cell genomes, suggesting that Kcr might be a gene-ON mark for actively transcribed regions of chromatin. However, functional studies of this novel histone PTM have been hindered by the fact that the regulating enzymes that catalyze the addition (i.e., writers) and removal (i.e., erasers) of Kcr are unknown. The identification of such writers and erasers is extremely challenging because interactions between PTMs and their regulating enzymes are usually weak and transient. Therefore, it is difficult to identify these interactions using classical affinity-based biochemical approaches. To tackle this difficulty, she extended the use of a chemical proteomics approach previously developed in my laboratory to comprehensively profile erasers for histone Kcr marks. Her study led to the identification of human Sirt3 as the FIRST eraser enzyme for histone Kcr. She found that Sirt3 can function as a decrotonylase to regulate histone Kcr dynamics in living cells. Her work not only demonstrated the physiological significance of histone Kcr, but also helped to unravel unknown cellular mechanisms controlled by Sirt3 that has been considered solely as a deacetylase before. Her work has received considerable attention in the fields of both chemistry and chromatin biology and was published in