20 years of histone lysine demethylases: From discovery to the clinic and beyond

Cell, Год журнала: 2025, Номер 188(7), С. 1747 - 1783

Опубликована: Апрель 1, 2025

Язык: Английский

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The mRNA export pathway licenses viral mimicry response and antitumor immunity by actively exporting nuclear retroelement transcripts

Science Translational Medicine, Год журнала: 2025, Номер 17(793)

Опубликована: Апрель 9, 2025

Nuclear retroelement transcripts (RTs), which can be elicited both transcriptionally and posttranscriptionally, form double-stranded RNA (dsRNA) in cytosol to trigger the viral mimicry response (VMR) antitumor immunity. However, strength of induced VMR varies tremendously across tumor types, underlying mechanisms remain poorly understood. Here, we demonstrate that mRNA export pathway modulates through actively exporting nuclear RTs for cytosolic dsRNA formation after their induction. Tumor cells hijack this process immune evasion aberrant coactivator-associated arginine methyltransferase 1 (CARM1) expression. Mechanistically, show cytoplasmic transportation by is counteracted exosome, cleaves multiple within pathway, including those encoding essential DExD-box helicase 39A (DDX39A) adaptor protein ALYREF. CARM1 enhances exosome activity attenuate two synergistic mechanisms: (i) activating several components (ii) posttranslationally methylating 6 subunit EXOSC1, protects it from proteasome-mediated degradation. Collectively, our study highlights critical active regulatory role transporting into triggering Furthermore, propose enhancing activity, either inhibition or modulation, could reinforce therapeutic agent-induced VMR, thus holding promise overcoming immunotherapy resistance.

Язык: Английский

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Catalytic-dependent and independent functions of the histone acetyltransferase CBP promote pioneer-factor-mediated zygotic genome activation

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

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The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(18), С. 13723 - 13723

Опубликована: Сен. 6, 2023

Epigenetics is a rapidly developing science that has gained lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute change gene expression while maintaining DNA sequence. The analysis these provides thorough insight into system from its development further functioning. strongly influenced by environmental factors, including known risk factors such as smoking, obesity, low physical activity. Similarly, conditions affecting local microenvironment cells, chronic inflammation, worsen prognosis additionally induce leading consolidation unfavorable changes. A deeper understanding epigenetics may provide an answer continuing strong clinical impact improving diagnostic capabilities, personalized medical approaches targeted therapeutic interventions. aim study was present selected pathways, their significance diseases, potential target specific conditions.

Язык: Английский

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Epigenetic regulation of heart failure

Current Opinion in Cardiology, Год журнала: 2024, Номер unknown

Опубликована: Апрель 8, 2024

Purpose of review The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding epigenetics. In this review, we provide an overview recent epigenetic mechanisms implicated in heart failure. Recent findings We focus major conceptual advances epigenetics as evidenced by humans mouse models significance modifications that catalyze them is also discussed. New from histone lysine demethylases demonstrate their regulating fetal gene expression, well aberrant expression adult hearts during HF. Similarly, relevance deacetylases inhibition failure role HDAC6 cardio-protection are Finally, LMNA (lamin A/C), a nuclear membrane protein interacts with chromatin form hundreds large domains known lamin-associated (LADs), 3D genome structure regulation Summary Epigenetic mechanism for responding stress environmental variation, enabling reactions both external internal stimuli, dysregulation can be pathological To gain thorough aid development targeted treatments failure, future research studying combined effects numerous changes warranted.

Язык: Английский

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Catalytic activity of Setd2 is essential for embryonic development in mice: establishment of a mouse model harboring patient-derived Setd2 mutation

Frontiers of Medicine, Год журнала: 2024, Номер 18(5), С. 831 - 849

Опубликована: Авг. 8, 2024

Язык: Английский

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WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 24, 2024

Abstract It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in context oncogenic stress. Here, we identify WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that interacts with replisome complex, disruption DPY30 resulting re-replication, damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, immunocompetent models, loss induced T infiltration immune-mediated clearance highly proliferating complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, expression was associated high tumor grade, worse prognosis, limited response to immune checkpoint blockade. Together, our findings indicate sustains genome stability suggest low intratumor levels may patients who will benefit from inhibitors.

Язык: Английский

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Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(13)

Опубликована: Май 30, 2023

Epigenetic status-altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these remain unresolved. In this study, we investigated dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss frequently mutated COMPASS family members MLL3 MLL4. CRISPR dropout screens MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression purine pyrimidine nucleotide synthesis pathways. Consistently, observed shift metabolic activity toward increased MLL3/4-KO mESCs. These also exhibited enhanced sensitivity to inhibitor lometrexol, which induced unique gene expression signature. RNA-Seq identified top MLL3/4 target genes coinciding with metabolism, tandem mass tag proteomic profiling further confirmed upregulation cells. Mechanistically, demonstrated compensation MLL1/COMPASS was underlying effects. Finally, tumors and/or MLL4 were highly sensitive lometrexol vitro vivo, both culture animal models cancer. Our results depicted targetable dependency epigenetic factor deficiency, providing molecular insight inform therapy for cancers alterations secondary dysfunction.

Язык: Английский

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KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability in Drosophila

Development, Год журнала: 2023, Номер 150(21)

Опубликована: Окт. 6, 2023

ABSTRACT Histone-modifying proteins play important roles in the precise regulation of transcriptional programs that coordinate development. KDM5 family interact with chromatin through demethylation H3K4me3 as well demethylase-independent mechanisms remain less understood. To gain fundamental insights into activities proteins, we examined essential single Drosophila Kdm5 ortholog during performs crucial functions larval neuroendocrine prothoracic gland, providing a model to study its role regulating key gene expression programs. Integrating genome binding and transcriptomic data, identify regulates genes required for function maintenance mitochondria, find loss causes morphological changes mitochondria. This is developmental KDM5, mitochondrial biogenesis transcription factor Ets97D, homolog GABPα, able suppress altered morphology lethality null animals. Together, these data establish KDM5-mediated cellular are normal development could contribute KDM5-linked disorders when dysregulated.

Язык: Английский

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Drosophila TET acts with PRC1 to activate gene expression independently of its catalytic activity

Science Advances, Год журнала: 2024, Номер 10(18)

Опубликована: Май 3, 2024

Enzymes of the ten-eleven translocation (TET) family play a key role in regulation gene expression by oxidizing 5-methylcytosine (5mC), prominent epigenetic mark many species. Yet, TET proteins also have less characterized noncanonical modes action, notably Drosophila , whose genome is devoid 5mC. Here, we show that activates genes required for larval central nervous system (CNS) development mainly catalytic-independent manner. Genome-wide profiling shows recruited to enhancer and promoter regions bound Polycomb group complex (PcG) proteins. We found interacts colocalizes on chromatin preferentially with repressor 1 (PRC1) rather than PRC2. Furthermore, PRC1 but not PRC2 activation target genes. Last, our results suggest binding activated interdependent. These data highlight importance noncatalytic function CNS.

Язык: Английский

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