Nature: First revealed the mechanism of histone lysine lactic acid (Kla) regulation

Today, the journal Nature published an epigenetic protein modification article by Professor Yingming Zhao's team at the University of Chicago, revealing for the first time the regulatory mechanism of histone lysine lactic acid (Kla) and demonstrating its role in changing macrophages in gene expression and microenvironmentThe authors first confirmed the presence of this modification in histones using a series of chemical and biochemical methodsThe 13C marker experiment showed that lactic acid base came from lactic acid, while lactic acid came from glucose degradationA series of experiments have shown that the concentration of endogenous lactic acid in cells can regulate the level of protein modification in this groupThe author explores the effect of histone Kla on cell function on the basis of macrophages as a model, and finds that the metabolic changes and the concentration of lactic acid after macrophages are activated, which leads to changes in histone Kla level and gene expressionIn vitro biochemical experiments show that the Kla donor is lactic acid acetyl coenzyme, and P300 purifase can catalyze histone Kla reactionInterestingly, in animal tumor model lingual experiments, the authors found that the level of histone Kla was associated with macrophage lactic acid concentration and hypoxia in tumor tissue, and therefore regulated from a memy M1 phenotype to an anti-meby M2 phenotypeAnd this regulatory effect depends on lactic acid to produce enzymes, LDHSThese results suggest that this epigenetic pathway plays an important role in regulating immune cell functiondrug source analysischemical modification of different sites of histones is an important mechanism of epigenetic regulation, methylation, acetylation, phosphorylation is well-known histone modification mechanismBut the lactic acid ation of histones was previously unknown, although lactic acid was a high-concentration metaboliteBecause cell metabolites cause histone lysine acetylation (Kac), the authors speculate that high intracellular concentrations of lactic acid may also lead to the ation of histone lysine lactic acid, and that polypeptides that use mass spectrometry to find several histone degradation serotins do appear to have Kla (molecular weight increase 72)To confirm this finding, the authors chemically synthesized a polypeptide control of lactic acid amide histones, resulting in HPLC retention time, MS/MS mapping and degradation products consistentThe identification of Kla antibodies also proves that histone lysine can indeed be lactic acid lycetic in cellsThe authors found a total of 28 Kla sites in human and mouse cellsby controlling enzyme activity and isotope markers of lactic acid biosynthesis, the authors found that histone Kla levels were positively correlated with lactic acid concentrations, which appeared to be a mechanism for cell monitoring and response to lactic acid changes in glycozymesetic solutions It has long been known that hypoxia alters cell metabolism patterns and induces glycolysis, and the authors find that hypoxia also increases Kla levels, but has no effect on Kac Inflammatory macrophages M1 are more dependent on aerobic glycolysis than anti-inflammatory M2 subtypes, and the authors found that glycolysis and lactic acid concentrations increased after activation of M1 macrophages with LPS, and histone Kla levels increased, and Kla more occurred in the lower kac regions RNA sequencing found that the expression of the pro-inflammatory gene increased rapidly after M1 activation but soon began to return to normal, while the expression of the genes that maintained the dynamic balance of tissue and the M2 gene, such as the wound healing gene (1223 genes in total), increased steadily and was highly correlated with histone Kla levels M0 macrophages activate similar results with inactivated gram-negative bacteria The authors call this mechanism the lactic acid timer, and macrophages are being ordered to initiate an acute immune response while beginning to use the Kla pathway to prepare for the mess By changing the lactic acid supply authors, the change in lactic acid concentration was the result of the change in Kla, but this did not prove that the Kla change was the trigger for changes in gene expression, and there is data suggesting that the newly awarded HIFa may also be a factor in this change The authors reacted lactic acid-based histones to enzymes in a noncellular environment, and found that similar gene transcription could indeed be induced epigenetic proteins are involved in regulating gene expression, so it directly affects cell function Kla is a new regulatory mechanism that only looks at macrophages, and the role of other cells has yet to be studied Lactic acid is a clear marker of cellular state because of its high concentration, and may also be an indicator of the cellular environment in which many biological processes are used A well-known phenomenon is the Warburg effect in tumors, where tumor tissue uses less efficient glycolysis as a source of energy even when oxygen is plentiful One theory is that the energy supply is less critical than the supply of materials when tumors expand, and that glycolysis can more efficiently scrape biosynthetic raw materials So the lactic acid content of tumor tissue is much higher than normal tissue, and it is conceivable that tumor cells may use this specific signal to design downstream operating procedures Proteins that produce, remove, and read the Kla mark may therefore become new anti-cancer targets, and it appears that the Kac mark with Kla well water does not violate the river has been marketed with multiple drugs this work also shows the power of mass spectrometry in proteomics The flux and sensitivity of this technique is amazing, and even the protein distribution on the cell surface can be measured at the single-cell level on a large scale Professor Zhao is the world's top expert in mass spectrometry technology analysis protein groups, and has achieved nothing in the field of protein modification Tumors are a disease of great heterogeneity Nevertheless, the most common common features of different cancers are the Warburg effect and the production of high concentrations of lactic acid Although the full solution to this cancer phenomenon is conducive to the pharmaceutical industry to use this cancer metabolic pattern to find new anti-cancer pathways Epigenetics is a highly concerned regulatory mechanism in the pharmaceutical industry, and today this work provides a new direction for finding high-quality drug targets Original title: Nature Research Article Reports New ExpressionGenetic Mechanisms - Histone Lactic Acid