Dataset Information

SIRT1/SIRT3 are robust lysine delactylases and SIRT1-mediated delactylation regulates glycolysis

ABSTRACT: Lysine lactylation (Kla), a newly identified epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, marks a pivotal juncture between metabolic pathways and gene regulation. The discovery of enzymes such as p300 and HDAC1/3 has been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Our investigation bridges these knowledge gaps by identifying SIRT1 and SIRT3 as key "erasers" of Kla, providing insights into their selective regulatory impact on both histone and non-histone proteins. Through a quantitative proteomic analysis in wildtype, SIRT1 knockout, and SIRT3 knockout HepG2 cells, we delineated a comprehensive landscape of Kla and lysine acetylation (Kac) sites. The results demonstrate a distinct specificity in the substrates modified by SIRT1 and SIRT3, underscoring their differentiated roles in cellular signaling pathways. Particularly, we highlight the role of specific Kla modifications, such as those on the M2 splice isoform of pyruvate kinase (PKM2), in modulating metabolic pathways and cell proliferation, thereby expanding the recognized implications of Kla beyond its epigenetic roles. Therefore, this study paves the way for deeper understanding of the functional phenotypes and mechanisms of Kla, offering new insights into its broader biological significance.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: He Huang

LAB HEAD: He Huang

PROVIDER: PXD050147 | Pride | 2025-05-06

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	Acetyl_K_Sites.txt	Txt
	HepG2_SIRT1KO_Kac_rep1.mzXML	Mzxml
	HepG2_SIRT1KO_Kac_rep2.mzXML	Mzxml
	HepG2_SIRT1KO_Kac_rep3.mzXML	Mzxml
	HepG2_SIRT1KO_Kla_rep1.mzXML	Mzxml

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Publications

Sirtuin 1/sirtuin 3 are robust lysine delactylases and sirtuin 1-mediated delactylation regulates glycolysis.

Du Runhua R Gao Yanmei Y Yan Cong C Ren Xuelian X Qi Shankang S Liu Guobin G Guo Xinlong X Song Xiaohan X Wang Hanmin H Rao Jingxin J Zang Yi Y Zheng Mingyue M Li Jia J Huang He H

iScience 20240910 10

Lysine lactylation (Kla), an epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, bridges metabolism and gene regulation. Enzymes such as p300 and HDAC1/3 have been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Here, we identify SIRT1 and SIRT3 as key "erasers" of Kla, shedding light on their selective regulation of both ...[more]

PMID: 39351192

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Project description:Beneficial effects of SIRT1 on healthspan are likely to be pleiotropic and may include effects on DNA methylation. We demonstrated recently that manipulating SIRT1 in human cells affected DNA methylation of a panel of test genes, and that genes with expression modified by dietary restriction corresponded with genes that underwent changes in DNA methylation during ageing. Here we tested the hypothesis that genes particularly susceptible to SIRT1-induced effects on DNA methylation across the genome map to genes for which DNA methylation changes during ageing. We increased or reduced SIRT1 expression in human intestinal (Caco-2) and vascular endothelial (HuVEC) cells by transient transfection with an expression construct or with siRNA, respectively. Effects on DNA methylation were measured by enriching for the methylated fraction then either sequencing (HuVEC) or hybridising to a human promoter microarray (Caco-2). Effects using these two different cell lines and techniques for analysis were remarkably consistent. Genes with a DNA methylation status affected by SIRT1 manipulation were enriched for those that undergo age-dependent changes in DNA methylation, thus supporting our hypothesis. Polycomb group protein target genes (PCGTs), which are suppressed by epigenetic mechanisms in stem cells and have been shown previously to correspond with loci particularly susceptible to age-related changes in DNA methylation, were over-represented within the set of genes showing altered DNA methylation in response to SIRT1 manipulation in both cell lines. We thus propose that effects of SIRT1 to extend healthspan include influences on the DNA methylation status of genes affected during ageing, in particular PCGTs. Analysis of methylation profiles of Caco-2 cells meeting the following conditions: SIRT1 overexpressed by transfection with pCMV6-ENTRY-SIRT1 (2 replicates), corresponding vector control (2 replicates), each of the siRNAs that target SIRT1 (1 & 2 replicates, respectively) and control siRNA (2 replicates).