DNA methylation in mammalian development and disease

Nature Reviews Genetics, Год журнала: 2024, Номер unknown

Опубликована: Авг. 12, 2024

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding how this modification contributes development, ageing disease. In particular, the past decade seen many exciting mechanistic discoveries that have substantially expanded our appreciation for generic, evolutionarily ancient can be incorporated into robust epigenetic codes. Here, we summarize current distinct landscapes emerge over mammalian lifespan discuss they interact with other regulatory layers support diverse functions. We then review rising interest in alternative patterns found during senescence somatic transition cancer. Alongside advancements single-cell long-read sequencing technologies, collective insights made across these fields offer new opportunities connect biochemical genetic features cell physiology, developmental potential phenotype. Review, Smith et al. describe development within key disease states, as well different methyltransferases interface histone modifications proteins create maintain them.

Язык: Английский

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Transposon–host arms race: a saga of genome evolution

Trends in Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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C2H2 proteins: Evolutionary aspects of domain architecture and diversification

BioEssays, Год журнала: 2024, Номер 46(8)

Опубликована: Июнь 14, 2024

The largest group of transcription factors in higher eukaryotes are C2H2 proteins, which contain C2H2-type zinc finger domains that specifically bind to DNA. Few well-studied however, demonstrate their key role the control gene expression and chromosome architecture. Here we review features domain architecture proteins likely origin fingers. A comprehensive investigation proteomes for presence with multiple clustered has revealed a difference between groups organisms. Unlike plants, metazoans clusters typically separated by linker TGEKP consensus sequence. average size varies substantially, even genomes metazoans, tendency increase combination SCAN, especially KRAB domains, reflecting increasing complexity regulatory networks.

Язык: Английский

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HIV Expression in Infected T Cell Clones

Viruses, Год журнала: 2024, Номер 16(1), С. 108 - 108

Опубликована: Янв. 11, 2024

The principal barrier to an HIV-1 cure is the persistence of infected cells harboring replication-competent proviruses despite antiretroviral therapy (ART). transcriptional suppression, referred as viral latency, foremost among determinants, it allows evade cytopathic effects virion production and killing by cytotoxic T lymphocytes (CTL) other immune factors. also governed cellular proliferation, innate essential capacity CD4+ that both sustains cell populations over time enables a robust directed response immunological threats. However, when infects cells, this for proliferation can enable surreptitious propagation without deleterious gene expression in latently cells. Over on ART, reservoir shaped with selective forces most often favoring clonally expanded transcriptionally quiescent proviruses. Moreover, if HIV latency incomplete or sporadically reversed clonal are replenished faster than they depleted, such could persist indefinitely contribute low-level persistent viremia during ART viremic rebound treatment withdrawn. In review, select genetic, epigenetic, cellular, determinants suppression expansion interdependencies these implications will be presented discussed.

Язык: Английский

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The KRAB-Zinc Finger protein ZKSCAN3 represses enhancers via embedded retrotransposons

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Summary Gene cis -regulatory sequences are increasingly recognised as containing “domesticated” transposable elements that impact their function. The KRAB Zinc Finger Protein (KZFP) family of transcription factors is typically associated with element silencing through establishment heterochromatin. Here, using acute protein depletion in embryonic stem cells, we reveal the KZFP ZKSCAN3 represses enhancer activity targeting enhancer-embedded retrotransposons and ZKSCAN3-mediated repression does not rely on induction ZKSCAN3, which exhibits strong genetic association neurodevelopmental disorder schizophrenia, operates during neural differentiation necessary for proper cell specification expression genes regulate axon guidance, neuronal motility pathfinding. These findings define an regulator uncover a heterochromatin-independent KZFP. Additionally, they exemplify how epigenetically regulates enhancers native setting highlight binders have shaped gene networks.

Язык: Английский

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The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

Опубликована: Фев. 17, 2025

Repression of retrotransposition is crucial for the successful fitness a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, an RNA-binding that expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it found to be essential maintaining pluripotency. cancer, L1TD1 expression highly correlative with malignancy progression as such considered potential prognostic factor tumors. However, its molecular role cancer remains largely unknown. Our findings reveal DNA hypomethylation induces HAP1 tumor cells. depletion significantly modulates both proteome transcriptome thereby reduces cell viability. Notably, associates L1 transcripts interacts ORF1p protein, facilitating retrotransposition. data suggest collaborates ancestral RNA chaperone, ensuring efficient retrotransposons, rather than directly impacting abundance targets. this way, might have important not during development but also tumorigenesis.

Язык: Английский

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Transposable elements may enhance antiviral resistance in HIV-1 elite controllers

Genome biology, Год журнала: 2025, Номер 26(1)

Опубликована: Фев. 23, 2025

Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated resistance, the and regulatory activity transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute control. To begin testing this hypothesis, we conduct a TE-centric analysis public multi-omics data from ECs other populations. We find cell transcriptome retrotranscriptome distinct healthy controls, on viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. categorize into four clusters chromatin accessibility profiles antiviral factors. Several TE families known immuno-regulatory differentially expressed Their positively correlates in negatively KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms network putative cis-regulatory genes involved restriction. propose that phenotype driven part by reduced KZNF-mediated repression specific TE-derived genes, heightening resistance against HIV-1. Our study reveals transcriptome, variable KZNF controllers, must be considered when deciphering control mechanisms.

Язык: Английский

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Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 16, 2025

Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 adenocarcinomas (LUAD) with deep whole-genome sequencing integrated multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. this group, observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, sex. from smokers showed abundance tobacco-related C:G>A:T mutations in KRAS plus short subclonal diversification. never early occurrence copy number alterations EGFR associated SBS5 SBS40a signatures. Tumors harboring exhibited long latency, particularly females European-ancestry (EU_N). EU_N, preceded the other including TP53 RBM10. Asian presented heterogeneous repetitive patterns inferred order. Importantly, found signature ID2 is marker previously unrecognized mechanism evolution. latency high L1 retrotransposon activity linked to promoter demethylation. These tumors aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden neoantigens, propensity develop metastasis, poor overall survival. Re-activated retrotransposition-induced mutagenesis contribute origin ID2, through regulation transcriptional factor ZNF695 , member KZFP family. The complex nature creates both challenges opportunities screening treatment plans.

Язык: Английский

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The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition

eLife, Год журнала: 2025, Номер 13

Опубликована: Март 20, 2025

Repression of retrotransposition is crucial for the successful fitness a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, an RNA-binding that expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it found to be essential maintaining pluripotency. cancer, L1TD1 expression highly correlative with malignancy progression as such considered potential prognostic factor tumors. However, its molecular role cancer remains largely unknown. Our findings reveal DNA hypomethylation induces HAP1 tumor cells. depletion significantly modulates both proteome transcriptome thereby reduces cell viability. Notably, associates L1 transcripts interacts ORF1p protein, facilitating retrotransposition. data suggest collaborates ancestral RNA chaperone, ensuring efficient retrotransposons, rather than directly impacting abundance targets. this way, might have important not during development but also tumorigenesis.

Язык: Английский

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Reactivation of retrotransposable elements is associated with environmental stress and ageing

Nature Reviews Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 2, 2025

Язык: Английский

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