Lactate-mediated histone lactylation promotes melanoma angiogenesis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE289136 | GEO | 2025/12/02
REPOSITORIES: GEO
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Project description:Lactate-mediated histone lactylation promotes melanoma angiogenesis
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Project description:Lactic acidosis, driven by hyperlactatemia, is a hallmark of severe Plasmodium falciparum malaria, yet its impact on parasitic life cycle and gene expression remains unclear. In mammalian cells, lactate influences transcription through histone lactylation, a novel post-translational modification. In this study, we demonstrate that P. falciparum undergoes lactate-derived lysine lactylation on nuclear proteins, including histones, histone variants, and AP2 transcription factors, with lactylation levels dynamically varying in response to physiological lactate ranges. Through CUT&RUN profiling, we show that elevated lactate enhances chromatin occupancy of lactylated proteins at promoters of genes involved in virulence and cytoadherence. Correspondingly, transcriptomic analyses demonstrated a suppression of these genes in response to elevated lactate, a pattern also evident in clinical isolates from severe malaria patients. Functionally, we demonstrate that high lactate reduces the binding ability of infected erythrocytes to CD36 receptor. Together, our findings reveal protein lactylation as a metabolite-responsive epigenetic mechanism in P. falciparum, linking host metabolic state to transcriptional reprogramming with direct implications for parasite virulence and disease pathogenesis.
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Project description:Chronic wounds, characterized by delayed healing and persistent inflammation, represent a major clinical burden with limited effective therapies. Inspired by the stereoselective interactions in biological systems, we developed an L-chiral hydrogel composed of self-assembled helical nanofibers from L-histidine derivatives, which preferentially enriches lactate to promote wound repair. Compared to D-chiral and racemic hydrogels, the L-chiral hydrogel significantly accelerated wound closure in rat models, achieving nearly 90% healing by day 14 and reducing healing time to 16-17 days. Transcriptomic and metabolomic analyses revealed enhanced wound response pathways and elevated lactate levels in the L-chiral group. Mechanistically, enriched lactate induced K57 lactylation of RNF123, mediated by AARS1, altering RNF123 conformation and weakening its binding to UBAC1. This modification enhanced ubiquitination and processing of NF-κB p105 into p50, inhibiting the NF-κB pathway and promoting angiogenesis via enhanced endothelial cell migration, tube formation, and sprouting. Rescue experiments with lactate inhibitor Oxamate and exogenous lactate confirmed the lactate-dependent mechanism. This study not only demonstrates a drug-free chiral biomaterial for efficient wound healing but also unveils the molecular role of lactate-mediated lactylation in mechanoregulating inflammation and vascularization, offering new insights for regenerative medicine.
2025-10-17 | GSE308113 | GEO
Project description:As a key metabolite of glycolysis, lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-DG or exogenous lactate Na-La to decrease or increase intracellular lactate levels, respectively. The results showed that 2-DG treatment promoted erythroid progenitors differentiation, blocked cell cycle and reduced colony-forming ability of CFU-E. In contrast, Na-La delayed erythroid progenitors differentiation and promoted CFU-E colony formation. We also found that lactate levels directly regulated H3K14la and H3K18la intensity. Furthermore, CUT&Tag results showed that the lost H3K14la peaks after 2-DG treatment were mainly enriched in promoter region and were associated with cell cycle and division. RNA-seq results showed that gene expression pattern was dramatically altered after 2-DG treatment, and differentially expressed genes were enriched in cell cycle and division process. Integrated analysis of CUT&Tag and RNA-seq revealed that gene expression was regulated by H3K14la, and CCNB1, CFL1, CENPA, SKA2 and GNAI2 gene expression were verified by RT-qPCR. In conclusion, our study reveals that lactate affects the cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.
2025-05-17 | GSE274165 | GEO
Project description:As a key metabolite of glycolysis, lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-DG or exogenous lactate Na-La to decrease or increase intracellular lactate levels, respectively. The results showed that 2-DG treatment promoted erythroid progenitors differentiation, blocked cell cycle and reduced colony-forming ability of CFU-E. In contrast, Na-La delayed erythroid progenitors differentiation and promoted CFU-E colony formation. We also found that lactate levels directly regulated H3K14la and H3K18la intensity. Furthermore, CUT&Tag results showed that the lost H3K14la peaks after 2-DG treatment were mainly enriched in promoter region and were associated with cell cycle and division. RNA-seq results showed that gene expression pattern was dramatically altered after 2-DG treatment, and differentially expressed genes were enriched in cell cycle and division process. Integrated analysis of CUT&Tag and RNA-seq revealed that gene expression was regulated by H3K14la, and CCNB1, CFL1, CENPA, SKA2 and GNAI2 gene expression were verified by RT-qPCR. In conclusion, our study reveals that lactate affects the cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.
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Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
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Project description:Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate. Highly glycolytic proliferating cells such as cancer cells take advantage of HK2 expression to accelerate glucose metabolism even in the presence of oxygen. This acceleration not only provides sufficient glycolytic intermediates to support the anabolic demands of the cells but also inevitably accompanies increased formation of metabolic end products such as lactate. Currently, the effect of lactate caused by HK2-mediated metabolic alteration is largely unknown. A recent study found that lactate plays a role in an epigenetic alteration known as histone lactylation. Here, using RNA-seq and CUT&Tag chromatin profiling, we study the effect of HK2 and lactate on gene expression via histone lactylation (H3K18la).
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Project description:Lactate Reprograms Glioblastoma Immunity through CBX3-regulated Histone Lactylation
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Project description:Cancer-augmented lactogenesis has been described by the Warburg effect, and is associated with several major hallmarks of neoplasia. However, the non-metabolic functions of elevated lactate in physiology and disease remain unknown. Here we report histone lysine lactylation as a new type of epigenetic mechanism and as a functional destination for lactate. Histone lactylation is induced under glycolytic conditions such as hypoxia and M1 macrophage polarization. In the late phase of M1 macrophage polarization, increases in histone lactylation but not acetylation mark M2-like genes for activation. Our findings suggest a feedback mechanism of the innate immune system to switch from proinflammation to resolution through histone Kla-associated gene expression. This mechanism is implemented by the coopted function of lactate and histone lactylation in metabolism and epigenetics. Together, our study opens a new avenue for understanding function of lactate and glycolysis underlined diverse pathophysiological conditions.
2019-08-06 | GSE115354 | GEO
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.
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