SMARCA5 links histone lactylation to metabolic reprogramming and immune evasion [CUT&Tag]
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ABSTRACT:
PROVIDER: PRJNA1314180 | ENA |
REPOSITORIES: ENA
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Project description:Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.
2025-09-15 | GSE307050 | GEO
Project description:Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.
2025-09-15 | GSE307047 | GEO
Project description:SMARCA5 links histone lactylation to metabolic reprogramming and immune evasion [ATAC-seq]
| PRJNA1314169 | ENA
Project description:To investigate the function of histone lactylation in ocular melanoma, we analyzed histone lactylation enrichment level in ocular melanoma by CUT&Tag.
2023-09-04 | GSE242018 | GEO
Project description:We hypothesize that the ISWI ATPase Smarca5 plays a role in hematopoietic stem cell development via its interaction partners, and to study the role, we used a mouse model with transgenic expression of SMARCA5 coupled with mass spectrometry analysis. The study uses transgenic SMARCA5 mouse model with conditional hypomorphic allele (lower expression on protein level compared to controls) incorporated into Rosa26 locus, transgenic allele uses endogenous Rosa26 promoter. The transgenic human SMARCA5 protein has a FLAG tag at its C-terminus, which allows specific immunoprecipitation and also differentiation from the endogenous protein (human and mouse SMARCA5 are almost identical at the protein level). To ensure the highest possible expression of the transgenic allele, we used a model that also had one endogenous Smarca5 allele deleted. Various organs (thymus, spleen, brain, kidney, liver, testes, muscle, fetal liver) were isolated from transgenic mice, lysed and then immunoprecipitated using anti-FLAG antibody. The immunoprecipitates were then analyzed using mass spectrometry to determine SMARCA5 interactomes in various tissues. Transgenic human SMARCA5 was confirmed to form all the expected complexes and capable of replacing the functions of the mouse protein. For details, see the publication of Turkova et al. 2024 in Communications Biology.
2024-06-22 | PXD049034 | Pride
Project description:Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boost histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la, and co-localizes with it on promoters of oncogenic genes. Notably, disrupting the association between DPF2 and histone lactylation through structure-guided mutation blunts those cancer-related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.
2024-06-17 | GSE267109 | GEO
Project description:Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyses, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172aloxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity.
2024-11-06 | GSE280695 | GEO
Project description:Cancer cells often rely on aerobic glycolysis for metabolism, and lactylation, a newly discovered post-translational modification, significantly impacts molecular processes. This study comprehensively analyzes lactylation's role in oral squamous cell carcinoma (OSCC), providing initial insights into its impact on progression. Oral squamous cell carcinoma cell lines, before and after lactate treatment, underwent CUT&TAG, ATAC, and transcriptomic sequencing. ChIP-qPCR and RT-qPCR validated results in OSCC tissues. Integrated analysis identified 217 genes with increased expression driven by lactylation in OSCC. Lactylation broadly impacted pathways in cancer, notably regulating PI3K/AKT and MAPK signaling. This pioneering study analyzes lactylation in OSCC, providing a global map of its regulation in oral squamous cell carcinoma from the perspective of chromatin-driven gene expression.
2024-08-20 | GSE249224 | 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:Aggregation of phosphorylated tau is associated with cognitive impairment in Alzheimers disease patients. In AD a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post-translational modification on proteins that conjugates lactyl groups to lysine residues known as lactylation. Our findings suggest that tau lactylation links metabolic dysregulation with tauopathies and could serve as a novel diagnostic and therapeutic target.
| MSV000095881 | MassIVE