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Histone Kla is regulated by cellular glycolysis

ABSTRACT: We have identified a new histone modification, which is derived from glycolysis end product, lactate. By SILAC-MS/MS based quantification, and U-13C6 glucose labeling experiments, we demonstrate that histone Kla is regulated by cellular glycolysis pathway

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Di Zhang

LAB HEAD: Yingming Zhao (Lab Head)

PROVIDER: PXD014870 | Pride | 2019-08-01

REPOSITORIES: Pride

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			Action	DRS
	MCF7_DCA_SILAC_Kac_IP.raw	Raw
	MCF7_DCA_SILAC_Kac_IP.zip	Other
	MCF7_DCA_SILAC_Kla_IP.raw	Raw
	MCF7_DCA_SILAC_Kla_IP.zip	Other
	MCF7_DCA_SILAC_Kla_Kac_protein_normalization.raw	Raw

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Publications

Metabolic regulation of gene expression by histone lactylation.

Zhang Di D Tang Zhanyun Z Huang He H Zhou Guolin G Cui Chang C Weng Yejing Y Liu Wenchao W Kim Sunjoo S Lee Sangkyu S Perez-Neut Mathew M Ding Jun J Czyz Daniel D Hu Rong R Ye Zhen Z He Maomao M Zheng Y George YG Shuman Howard A HA Dai Lunzhi L Ren Bing B Roeder Robert G RG Becker Lev L Zhao Yingming Y

Nature 20191023 7779

The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases<sup>1,2</sup>. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functi ...[more]

PMID: 31645732

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Lysine lactylation regulates biofilm formation of streptococcus mutans

Project description:Lactate produced in glycolysis has recently been discovered to modify lysine residues on eukaryotic proteins, a post-translational modification (PTM) called lysine lactylation (Kla). This modification not only participates in regulating gene expression through lactylation of histones, but also impacts the function of non-histone proteins. However, lactylation in prokaryotes has not been reported. Here, we report the identification of 1869 lysine lactylation sites in 465 proteins in the cariogenic organism Streptococcus mutans using a newly developed 4-dimensional label-free quantitative proteomic approach, representing the first Kla dataset in prokaryotes. Combining quantitative analysis, we report that the modification levels of 282 sites from 124 proteins increased by over 1.5-fold, and 80 sites from 52 proteins decreased by over 0.67-fold in the biofilm growth state. These results provide a systematic perspective of the distribution and function of Kla and improve our understanding of the role of lactate in the metabolic regulation of prokaryotes.

2023-08-24 | PXD037027 | Pride

Systematic Identification of the Lysine lactylation in the Protozoan Parasite Toxoplasma gondii

Project description:Lysine lactylation (Kla) is a new posttranslational modification (PTM) identified in histone and nonhistone proteins of several eukaryotic cells that directly activate gene expression and DNA replication. However, very little is known about their scope and cellular distribution in apicomplexan parasites that are important to public and animal health. Toxoplasma gondii, the agent of toxoplasmosis, is one of obligate intracellular apicomplexan parasite that can infect all kinds of nucleated cells of animals and humans. Using this parasite as model organism, herein, we produced the first global lysine lactylome profile through LC-MS/MS. Overall, a total of 983 Kla sites occurred on 523 lactylated proteins were identified in Toxoplasma tachyzoites, the acute toxoplasmosis-causing stage. Bioinformatics analysis revealed that these lactylated proteins are evolutionarily conserved and involved in a wide variety of cellular functions such as energy metabolism, gene regulation and protein biosynthesis. Moreover, the results from subcellular localization analysis and IFA showed that the majority of lactylated T. gondii proteins localized in the nucleus, indicating a potential impact of Kla on gene regulation. Notably, an extensive batch of parasite-specific proteins unique to Apicomplexa is lactylated in T. gondii. Our findings revealed that Kla was widespread in the early branching eukaryotic cell, and that lactylated proteins, including a crowd of unique parasite proteins, were involved in a remarkably diverse array of cellular functions. These valuable data will improve our understanding of the evolution of Kla while potentially providing novel therapeutic avenues.

2022-06-09 | PXD031526 | Pride

SILAC experiment quantifying the proteomics of WT and HBO1-KO HeLa

Project description:Lysine lactylation (Kla) links metabolism and gene regulation and plays a key role in multiple biological processes. We report that HBO1 functions as a lysine lactyltransferase to regulate transcription. Quantitative proteomic analysis further revealsed 95 endogenous Kla sites targeted by HBO1, with the majority located on histones.

2024-04-13 | PXD051415 | Pride

Identification of lysine-lactylated substrates in gastric cancer cells

Project description:Lysine lactylation is a newly discovered post-translational modification (PTM) in histones and plays important roles in regulating gene expression. However, Kla in non-histone proteins in mammal is still unclear. Here, an analysis of lactylated proteins in gastric cancer AGS cells by using LC-MS/MS was conducted, and 2375 Kla sites on 1014 proteins were identified.

2022-08-11 | PXD033991 | Pride

The genome-wide targeting of H3K18la in H1299 cells

Project description:L-lactate was reported as a precursor that can label and stimulate histone lysine-N-L-lactylation (Kla), which represents a new epigenetic mark affecting gene expression directly via histone PTMs under conditions of high glycolysis, such as the Warburg effect. To investigate the genome-wide targeting of H3K18la, we performed ChIP-seq in H1299 cells using anti-H3K18la antibody. 50.6% of the H3K18la binding sites displayed enrichment close to -1kb promoter of genes. More importantly, our ChIP-seq data showed that H3K18la is enriched in many genes that related with replication processes, highlighted the importance of histone Kla involved in DNA replication.

2023-07-30 | GSE207814 | GEO

Analysis of Lysine Lactylation in CD4+ T cells of normal and EAU mouse

Project description:Primary CD4+ T cells were isolated from normal and EAU mice spleens and used for lactylome analysis.

2023-08-29 | PXD040514 | Pride

A DNA polymerase ? accessory protein, Mcl1, is required for propagation of centromere structures in fission yeast

Project description:Specialized chromatin exists at centromeres and must be precisely transmitted during DNA replication. The mechanisms involved in the propagation of these structures remain elusive. Fission yeast centromeres are composed of two chromatin domains: the central CENP-ACnp1 kinetochore domain and flanking heterochromatin domains. Here we show that fission yeast Mcl1, a DNA polymerase ? (Pol?) accessory protein, is critical for maintenance of centromeric chromatin. In a screen for mutants that alleviate both central domain and outer repeat silencing, we isolated several cos mutants, of which cos1 is allelic to mcl1. The mcl1-101 mutation causes reduced CENP-ACnp1 in the central domain and an aberrant increase in histone acetylation in both domains. These phenotypes are also observed in a mutant of swi7+, which encodes a catalytic subunit of Pol?. Mcl1 forms S-phase-specific nuclear foci, which colocalize with those of PCNA and Pol?. These results suggest that Mcl1 and Pol? are required for propagation of centromere chromatin structures during DNA replication. Keywords: ChIP-chip analysis, S. pombe Antibodies used were ?-acetyl-histone H4 antiserum (Upstate) and ?-histone H4 pan antibody (Upstate). ChIP-on-chip was carried out using IVT amplification method. ChIP-chip data were comfirmed by real-time PCR.

2008-07-22 | E-GEOD-11102 | biostudies-arrayexpress

Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

Project description:Hypoxia promotes tumorigenesis and lactate accumulation in esophageal squamous cell carcinoma (ESCC). Lactate can induce histone lysine lactylation (Kla, a recently-identified histone marks) to regulate transcription. However, the functional consequence of histone Kla under hypoxia in ESCC remains to be explored. Here, we reveal that hypoxia facilitates histone H3K9la to enhance LAMC2 transcription for proliferation of ESCC. We found that global level of Kla was elevated under hypoxia, and thus identified the landscape of histone Kla in ESCC by quantitative proteomics. Furthermore, we show a significant increase of H3K9la level induced by hypoxia. Next, MNseq ChIP-seq and RNA-seq analysis suggest that H3K9la is enriched at the promoter of cell junction genes. Finally, we demonstrate that the histone H3K9la facilitates the expression of LAMC2 for ESCC invasion by in vivo and in vitro experiments. Briefly, our study reveal a vital role of histone Kla triggered by hypoxia in cancer.

2024-05-22 | GSE255352 | GEO

Characterization of protein lactylation in relation to cardiac metabolic reprogramming in neonatal mouse hearts

Project description:In mammals, the neonatal heart regenerates within a short time after birth, but adults lack this ability. We have shown that metabolic reprogramming is critical for cardiomyocyte proliferation in the neonatal heart. Herein, we revealed that cardiac metabolic reprogramming could be regulated by altering global protein lactylation. 4D label-free proteomics and Kla omics were performed in postnatal Day 1 (P1), 5 (P5), and 7 (P7) mouse hearts, 2297 Kla sites from 980 proteins were identified, and 1262 Kla sites from 409 proteins were quantified. Functional clustering analysis of proteins with altered Kla sites revealed that the proteins were mainly involved in metabolic processes. The Kla levels in several fatty acid oxidation-related proteins showed high expression at P5, while glycolysis and cell cycle-related proteins were sustainedly decreased from P1-P7. Furthermore, we verified the Kla levels of several differentially modified proteins, including ACAT1, ACADL, PKM and NPM1, by coimmunoprecipitation and Western blotting. Overall, we reported the first comprehensive Kla map in the neonatal mouse heart, which will aid in understanding the regulatory network of metabolic reprogramming and cardiac regeneration.

2024-07-02 | PXD039257 | Pride

Quantitative Proteome and Lysine Lactylome of Proteins within Pathological Site of Rotator Cuff Tendinopathy

Project description:Lysine lactylation (Kla) is a newly discovered posttranslational modification showing the addition of an L-lactate-derived lactyl group to the lysine residue. Histone lactylation has been found to regulate the downstream genes expression involved in the process of infection clearance, homeostasis retore, and tumorigenesis. Like other metabolite mediated PTMs, which the cellular levels of these metabolites affect the stoichiometry of the corresponding PTMs, the level of Kla also responds to the intracellular lactate concentration in a dose-dependent fashion associated with glycolysis metabolism. It has long been noted that manipulation of glycolysis metabolism could affect the tendon cell function, tendon homeostasis, and healing process of tendon.Nonetheless, the lactylation sites and regulations in tendinopathy remain unexplored.

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