Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones

Cell, Journal Year: 2023, Volume and Issue: 186(13), P. 2748 - 2764.e22

Published: June 1, 2023

Language: Английский

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An epigenetic barrier sets the timing of human neuronal maturation

Nature, Journal Year: 2024, Volume and Issue: 626(8000), P. 881 - 890

Published: Jan. 31, 2024

Abstract The pace of human brain development is highly protracted compared with most other species 1–7 . maturation cortical neurons particularly slow, taking months to years develop adult functions 3–5 Remarkably, such timing retained in derived from pluripotent stem cells (hPSCs) during vitro differentiation or upon transplantation into the mouse 4,8,9 Those findings suggest presence a cell-intrinsic clock setting neuronal maturation, although molecular nature this remains unknown. Here we identify an epigenetic developmental programme that sets maturation. First, developed hPSC-based approach synchronize birth which enabled us define atlas morphological, functional and We observed slow unfolding programmes, limited by retention specific factors. Loss function several those factors enables precocious Transient inhibition EZH2, EHMT1 EHMT2 DOT1L, at progenitor stage primes newly born rapidly acquire mature properties differentiation. Thus our reveal rate set well before neurogenesis through establishment barrier cells. Mechanistically, holds transcriptional programmes poised state gradually released ensure prolonged timeline neuron

Language: 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, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 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.

Language: Английский

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Methylation across the central dogma in health and diseases: new therapeutic strategies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 24, 2023

The proper transfer of genetic information from DNA to RNA protein is essential for cell-fate control, development, and health. Methylation DNA, RNAs, histones, non-histone proteins a reversible post-synthesis modification that finetunes gene expression function in diverse physiological processes. Aberrant methylation caused by mutations or environmental stimuli promotes various diseases accelerates aging, necessitating the development therapies correct disease-driver imbalance. In this Review, we summarize operating system across central dogma, which includes writers, erasers, readers, reader-independent outputs. We then discuss how dysregulation contributes neurological disorders, cancer, aging. Current small-molecule compounds target modifiers show modest success certain cancers. methylome-wide action lack specificity lead undesirable biological effects cytotoxicity, limiting their therapeutic application, especially with monogenic cause different directions changes. Emerging tools capable site-specific manipulation hold great promise solve dilemma. With refinement delivery vehicles, these new are well positioned advance basic research clinical translation field.

Language: Английский

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R-loop-dependent promoter-proximal termination ensures genome stability

Nature, Journal Year: 2023, Volume and Issue: 621(7979), P. 610 - 619

Published: Aug. 9, 2023

Abstract The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1,2 . Here we identify a stable association between the genome-stability regulator sensor single-stranded DNA (SOSS) 3 Integrator-PP2A (INTAC) 4–6 Through SSB1-mediated recognition DNA, SOSS–INTAC stimulates promoter-proximal termination attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced instability. SOSS–INTAC-dependent attenuation enhanced by ability SSB1 form liquid-like condensates. Deletion NABP2 (encoding SSB1) or introduction cancer-associated mutations into its intrinsically disordered region leads pervasive accumulation R-loops, highlighting surveillance function that enables timely at promoters constrain R-loop ensure stability.

Language: Английский

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INTAC endonuclease and phosphatase modules differentially regulate transcription by RNA polymerase II

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(10), P. 1588 - 1604.e5

Published: April 19, 2023

Gene expression in metazoans is controlled by promoter-proximal pausing of RNA polymerase II, which can undergo productive elongation or termination. Integrator-PP2A (INTAC) plays a crucial role determining the fate paused polymerases, but underlying mechanisms remain unclear. Here, we establish rapid degradation system to dissect functions INTAC endonuclease and phosphatase modules. We find that both catalytic modules function at most if not all active promoters enhancers, yet differentially affect fate. The module induces termination, with its disruption leading accumulation elongation-incompetent polymerases downregulation highly expressed genes, while elongation-competent accumulate lowly genes non-coding elements, their upregulation. primarily prevents release limits transcriptional activation, especially for genes. Thus, have unexpectedly general distinct roles dynamic control.

Language: Английский

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Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(6), P. 1168 - 1180

Published: May 9, 2024

Abstract Chromatin modifications are linked with regulating patterns of gene expression, but their causal role and context-dependent impact on transcription remains unresolved. Here we develop a modular epigenome editing platform that programs nine key chromatin modifications, or combinations thereof, to precise loci in living cells. We couple this single-cell readouts systematically quantitate the magnitude heterogeneity transcriptional responses elicited by each specific modification. Among these, show installing histone H3 lysine 4 trimethylation (H3K4me3) at promoters can causally instruct hierarchically remodeling landscape. further dissect how DNA sequence motifs influence marks, identifying switch-like attenuative effects within distinct cis contexts. Finally, examine interplay combinatorial revealing co-targeted H3K27 (H3K27me3) H2AK119 monoubiquitination (H2AK119ub) maximizes silencing penetrance across single Our precision-perturbation strategy unveils principles modification(s) dissects quantitative calibrated contextual interactions.

Language: Английский

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Targeting NPM1 Epigenetically Promotes Postinfarction Cardiac Repair by Reprogramming Reparative Macrophage Metabolism

Circulation, Journal Year: 2024, Volume and Issue: 149(25), P. 1982 - 2001

Published: Feb. 23, 2024

Reparative macrophages play a crucial role in limiting excessive fibrosis and promoting cardiac repair after myocardial infarction (MI), highlighting the significance of enhancing their reparative phenotype for wound healing. Metabolic adaptation orchestrates phenotypic transition macrophages; however, precise mechanisms governing metabolic reprogramming remain poorly understood. In this study, we investigated NPM1 (nucleophosmin 1) shift context MI explored therapeutic effect targeting ischemic tissue repair.

Language: Английский

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Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity

BMJ Oncology, Journal Year: 2024, Volume and Issue: 3(1), P. e000154 - e000154

Published: Feb. 1, 2024

Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge cancer treatment is tumour microenvironment particular hypoxia (low oxygen levels), contributes progression immune evasion. At cellular level, this primarily governed by hypoxia-inducible factor (HIF). HIF a transcription that orchestrates responses low levels, driving angiogenesis, metabolic adaptation regulation. HIF's dysregulation frequently observed various types correlates with increased aggressiveness, metastasis, resistance therapy poor patient prognosis. Consequently, understanding mechanisms underlying activation downstream effects has become crucial developing targeted therapies for improving outcomes represents key step towards precision medicine. Recent advancements drug development have led emergence inhibitors, aim disrupt HIF-driven processes providing benefit. Here, we provide review molecular through promotes growth resistance, emphasising potential clinical benefits HIF-targeted therapies. This will discuss opportunities associated translating inhibition into practice, including ongoing trials future directions HIF-based treatments.

Language: Английский

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Roles of H3K4 methylation in biology and disease

Trends in Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Epigenetic modifications, including posttranslational modifications of histones, are closely linked to transcriptional regulation. Trimethylated H3 lysine 4 (H3K4me3) is one the most studied histone owing its enrichment at start sites transcription and association with gene expression processes determining cell fate, development, disease. In this review, we focus on recent studies that have yielded insights into how levels patterns H3K4me3 regulated, contributes regulation specific phases such as RNA polymerase II initiation, pause–release, heterogeneity, consistency. The conclusion from these by itself regulates precise essential for normal development preventing

Language: Английский

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