Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells

Molecular Cell, Год журнала: 2022, Номер 82(9), С. 1660 - 1677.e10

Опубликована: Март 22, 2022

Язык: Английский

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RNA modifications: importance in immune cell biology and related diseases

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Сен. 22, 2022

RNA modifications have become hot topics recently. By influencing processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune abnormality in human diseases is also a research focus progressing rapidly these years. Studies demonstrated that participate the multiple biological processes cells, development, differentiation, activation, migration, polarization, thereby modulating responses are involved some related diseases. In this review, we present existing knowledge functions underlying mechanisms modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, summarize their roles Via regulating can pathogenesis diseases, such cancers, infection, inflammatory autoimmune We further highlight challenges future directions based on knowledge. All all, review will provide helpful well novel ideas for researchers area.

Язык: Английский

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Regulation of axonal regeneration after mammalian spinal cord injury

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 24(6), С. 396 - 413

Опубликована: Янв. 5, 2023

Язык: Английский

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Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Авг. 30, 2023

Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis poorly understood. The heritability estimate of MDD 30-40%, suggesting genetics alone do not account for most the risk major depression. Another factor known to associate with involves environmental stressors such as childhood adversity recent life stress. Recent studies have emerged show biological impact factors in other stress-related disorders mediated by variety epigenetic modifications. These modification alterations contribute abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission neuroglia dysfunction, which are involved pathophysiology MDD. Furthermore, marks been associated diagnosis treatment evaluation modifications holds promise further understanding heterogeneous etiology complex phenotypes MDD, may identify new therapeutic targets. Here, we review preclinical clinical findings, including DNA methylation, histone modification, noncoding RNA, RNA chromatin remodeling In addition, elaborate on contribution these mechanisms pathological trait variability depression discuss how can be exploited purposes.

Язык: Английский

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Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Янв. 10, 2023

Accumulated evidence highlights the significance of crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding 5mC m6A regulators in hepatocellular carcinoma (HCC).Pan-cancer genomic was presented at transcriptomic, genomic, epigenetic, other multi-omics levels. Hub were summarized to define an module eigengene (EME), which reflected both pre- post-transcriptional modifications.5mC interacted with one another multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled greatly optimize risk stratification accurately predict HCC patients' clinical outcomes progression. Additionally, predicted responses mainstream therapies (TACE sorafenib) immunotherapy as well hyper-progression. In vitro, cooperatively weakened apoptosis facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion epithelial-to-mesenchymal transition (EMT) cells. remarkably linked potential extrinsic intrinsic immune escape high might contribute reduced copy number gain/loss frequency. Finally, determined therapeutic compounds druggable targets (TUBB1 P2RY4) for patients EME.Our findings suggest that may result from unique synergistic combination 5mC-epigenetic mechanism mixed m6A-epitranscriptomic mechanism, their defines response pharmacogenomic landscape.

Язык: Английский

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Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury

Redox Biology, Год журнала: 2024, Номер 74, С. 103194 - 103194

Опубликована: Май 16, 2024

Elevated lactate levels are a significant biomarker of sepsis and positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is leading cause poor prognosis in clinical patients. However, the underlying mechanisms lactate's involvement sepsis-associated ALI remain unclear. In this study, we demonstrate that regulates N6-methyladenosine (m6A) modification by facilitating p300-mediated H3K18la binding to METTL3 promoter site. The METTL3-mediated m6A enriched ACSL4, its mRNA stability regulated through YTHDC1-dependent pathway. Furthermore, short-term stimulation upregulates which promotes mitochondria-associated ferroptosis. Inhibition knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis alveolar epithelial cells mitigates mice. Our findings suggest induces via GPR81/H3K18la/METTL3/ACSL4 axis during ALI. These results reveal histone lactylation-driven mechanism inducing modification. Targeting represents promising therapeutic strategy for patients

Язык: Английский

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Nuclear m6A reader YTHDC1 promotes muscle stem cell activation/proliferation by regulating mRNA splicing and nuclear export

eLife, Год журнала: 2023, Номер 12

Опубликована: Март 9, 2023

Skeletal muscle stem cells (also known as satellite [SCs]) are essential for regeneration and the regenerative activities of SCs intrinsically governed by gene regulatory mechanisms, but post-transcriptional regulation in remains largely unknown. N(6)-methyladenosine (m6A) modification RNAs is most pervasive highly conserved RNA eukaryotic cells; it exerts powerful impact on almost all aspects mRNA processing that mainly endowed its binding with m6A reader proteins. In this study, we investigate previously uncharacterized roles YTHDC1, an mouse SCs. Our results demonstrate YTHDC1 regulator SC activation proliferation upon acute injury-induced regeneration. The induction indispensable proliferation; thus, inducible depletion abolishes capacity. Mechanistically, transcriptome-wide profiling using LACE-seq both C2C12 myoblasts identifies m6A-mediated targets YTHDC1. Next, splicing analysis defines m6A-YTHDC1. Furthermore, nuclear export also leads to identification potential m6A-YTHDC1 myoblasts;interestingly, some mRNAs can be regulated at levels. Lastly, map interacting protein partners unveil a myriad factors governing splicing, export, transcription, among which hnRNPG appears bona fide partner Altogether, our findings uncover factor controlling ability through multifaceted mechanisms myoblast cells.

Язык: Английский

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Profiling the epigenome using long-read sequencing

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Язык: Английский

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Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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The role of protein lactylation: A kaleidoscopic post-translational modification in cancer

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, has been also described non-histone proteins, playing pivotal role transcriptional activation, protein function, cellular processes. Two major sources of the lactyl moiety have currently distinguished: L-lactyl-CoA (precursor L-lactyl moiety) S-D-lactylglutathione D-lactyl moiety), which enable enzymatic non-enzymatic mechanisms lactylation, respectively. Although specific writers, erasers, readers this are still unclear, acetyltransferases deacetylases proposed as crucial mediators lactylation. Remarkably, exerts significant influence cancer-related pathways, thereby shaping behavior during malignant transformation metastatic cascade. Hence, recent insights into underscore its growing potential tumor biology, targeting is emerging opportunity for treatment.

Язык: Английский

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