Scientific Reports
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2025
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IF 3.9
Xu Qiuling,Liu Zhuoxi,Wang Liyuan,Liu Guoyang,Zhao Long,Yue Hui,Liu Yong
Diabetic cardiomyopathy (DCM) requires a systematic approach for effective management. Focusing on key signaling pathways in myocardial fibrosis could offer novel therapeutic approaches for DCM. The objective of this research is to investigate new biomarker and the underlying mechanisms by which baicalin intervenes in the progression of DCM. Swiss Target Prediction databases and weighted correlation network analysis (WGCNA) were employed to collect and analyze targets of baicalin and DCM. Intersection targets were obtained through venn online website, network visualization was conducted through STRING database and Cytoscape 3.7.2 software. Molecular docking validation was completed via AutoDock Vina software. Western blotting, RT-qPCR and histology were carried out to validate the direct targets of baicalin and explore the molecular mechanism during DCM progression. In mice induced to DCM, we observed that disruptor of telomeric silencing 1-like (DOT1L) was upregulated. Baicalin (BC) reduced myocardial fibrosis in mice as indicated by the reduced expression levels of fibrosis markers COL-1 and TGF-β. The inhibitory effect of BC was reversed by overexpressed DOT1L and further enhanced by silenced DOT1L. Our results indicate that cardiomyocyte DOT1L exerts a pathogenic role in DCM and BC specifically targets DOT1L/COL-1 signaling to reduce myocardial fibrosis in DCM.
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DOI
PubMed
高影响因子
Cell Reports
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2021
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IF 9.423
Tanjing Song,Qingli Zou,Yingying Yan,Suli Lv,Neng Li,Xuefeng Zhao,Xianyun Ma,Haigang Liu,Borui Tang,Lidong Sun
Summary Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Immunology
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2026
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IF 7
Xiwu Rao,Xiangjun Qi,Zhiqiang Chen,Jingrui Wang,Xiaoshu Chai,Lizhu Lin
The histone methyltransferase DOT1L, the sole enzyme catalyzing H3K79 methylation, is increasingly implicated in cancer progression, yet its role in shaping the tumor immune microenvironment (TME) remains unclear. Here, we demonstrate that DOT1L orchestrates immune evasion in lung adenocarcinoma (LUAD) through epigenetic activation of multiple immune checkpoints. Integrative analysis of TCGA and single-cell RNA-seq data revealed that high DOT1L expression correlates with poor prognosis, diminished cytotoxic immune-cell infiltration, and upregulation of inhibitory checkpoints (PD-L1, PD-1, LAG3, CD276, etc.). Mechanistically, ChIP-seq identified DOT1L-mediated H3K79me2 enrichment at promoters of JAK1/STAT3 genes, and some immune checkpoints, including LAG3, CD276, etc. Pharmacological DOT1L inhibition (SGC0946) suppressed the JAK1/STAT3/PD-L1 axis, reduced PD-1+ T cells in a vitro immune microenvironment. In vivo , SGC0946 attenuated lung metastasis, improved survival, and remodeled the TME by downregulating PD-L1, LAG3, and CD276 expression, reduced PD-1+ T cells subsets, and alongside with enhanced TNF-α, IFN-γ production. Clinical LUAD specimens further validated the correlation between DOT1L expression, STAT3 activation, and checkpoint upregulation, particularly in metastatic disease. Our findings identify DOT1L as an epigenetic linchpin of immune suppression.
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产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
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2026
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IF 4.4
Guozhen Ni,Ning Ma,Jian Xu
IntroductionApigenin (API) has been utilized in the treatment of atherosclerosis. Senescent macrophages exhibit a senescence-associated secretory phenotype (SASP), which plays a critical role in the progression of atherosclerosis. IL1A expression is thought to be involved in the transition of macrophages to the SASP phenotype. This study explored the effect of API on the atherosclerosis-related SASP in macrophages and the underlying mechanism.MethodsMacrophages were treated with different concentrations of API. The expression of DOT1-like histone lysine methyltransferase (DOT1L) was manipulated in macrophages. Stimulation with lipopolysaccharide (LPS) was conducted to induce the SASP. Macrophage senescence was detected by senescence-associated-β-galactosidase staining. The expressions of interleukin 1 α (IL1A), DOT1L, and markers related to senescence, the SASP, and inflammation in macrophages were assessed. Chromatin immunoprecipitation was performed to check DOT1L-mediated H3K79me2 enrichment at the promoter of IL1A.ResultsAPI treatment effectively reduced cellular senescence in LPS-exposed macrophages. Furthermore, it downregulated markers associated with senescence, SASP, and inflammation, while upregulating the anti-inflammatory cytokine IL-10. Moreover, LPS-induced DOT1L and H3K79me2 enrichment at the IL1A promoter, as well as DOT1L and IL1A upregulation in macrophages, were hindered by API. DOT1L overexpression counteracted API’s effects, including its ability to inhibit senescence, downregulate senescence/SASP/inflammation markers, upregulate IL-10, and prevent H3K79me2 and DOT1L binding at the IL1A promoter. DOT1L silencing reduced LPS-induced senescence, SASPs, and H3K79me2 enrichment in macrophages.ConclusionAPI inhibits DOT1L-mediated H3K79me2 enrichment to downregulate IL1A, thus reducing the SASP of macrophages.
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高影响因子
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