Transposable elements as genome regulators in normal and malignant haematopoiesis

Blood Cancer Journal, Journal Year: 2025, Volume and Issue: 15(1)

Published: May 6, 2025

Abstract Transposable elements (TEs) constitute over half of the human genome and have played a profound role in evolution. While most TEs lost ability to transpose, many retain functional that serve as drivers innovation, including emergence novel genes regulatory elements. Recent advances experimental bioinformatic methods provided new insights into their roles biology, both health disease. In this review, we discuss multifaceted haematopoiesis, highlighting contributions normal pathological contexts. influence gene regulation by reshaping gene-regulatory networks, modulating transcriptional activity, creating These activities play key maintaining haematopoietic processes supporting cellular regeneration. However, haematological malignancies, TE reactivation can disrupt genomic integrity, induce structural variations, dysregulate programmes, thereby driving oncogenesis. By examining impact activity on variation, highlight pivotal cancers.

Language: Английский

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Synchronous L1 retrotransposition events promote chromosomal crossover early in human tumorigenesis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 27, 2024

Abstract L1 retrotransposition is a significant source of genomic variation in human epithelial tumours, which can contribute to tumorigenesis. However, fundamental questions about the causes and consequences activity cancer genomes remain unresolved, primarily due limitations short-read sequencing technologies. Here, we employ multiplatform sequencing, with an emphasis on long reads, analyse fine selection 10 tumours exhibiting high rates somatic retrotransposition, encompassing over 6000 events. The analysis locus-specific single-nucleotide variants reveals novel panorama loci activity. Furthermore, examination internal structure L1s uncovers mechanisms behind their inactivation. A hidden landscape chromosomal aberrations emerges light where reciprocal translocations mediated by insertion represent frequent Resolution bridges’ configuration elucidates formation, typically two independent, but synchronous, insertions drive exchange between non-homologous chromosomes. Timing analyses indicate that early driver instability, active before first whole-genome doubling event. Overall, these findings highlight as more contributor tumour genome plasticity than previously recognized, extending its impact beyond simple insertional mutagenesis.

Language: Английский

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From the genome's perspective: Bearing somatic retrotransposition to leverage the regulatory potential of L1 RNAs

BioEssays, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 9, 2024

Transposable elements (TEs) are mobile genomic constituting a big fraction of eukaryotic genomes. They ignite an evolutionary arms race with host genomes, which in turn evolve strategies to restrict their activity. Despite being tightly repressed, TEs display precisely regulated expression patterns during specific stages mammalian development, suggesting potential benefits for the host. Among TEs, long interspersed nuclear element (LINE-1 or L1) has been found be active neurons. This activity prompted extensive research into its possible role cognition. So far, no cause-effect relationship between L1 retrotransposition and brain functions conclusively identified. Nevertheless, accumulating evidence suggests that interactions RNAs RNA/DNA binding proteins encode messages cells utilize activate repress entire transcriptional programs. We summarize recent findings highlighting at non-coding level early embryonic development. propose hypothesis mutualistic mRNAs cell. In this scenario, tolerate certain rate leverage regulatory effects L1s as on potentiating mitotic potential. turn, benefit from cell's proliferative state increase chance mobilize.

Language: Английский

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Transposable element 5mC methylation state of blood cells predicts age and disease

Nature Aging, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. 5-methylcytosine (5mC) is one of main epigenetic modifications by which silenced and has used train highly accurate age predictors. Yet, common criticism such predictors they lack interpretability. In this study, we investigate changes TE 5mC methylation occur aging human blood using published array data. We find evolutionarily young long interspersed nuclear 1 (L1s), only known capable autonomous transposition humans, undergo fastest loss methylation, suggesting an active mechanism de-repression. The same L1s also showed preferential gain chromatin accessibility but not expression. terminal repeat retrotransposons THE1A THE1C very rapid loss. then show can be trained on both individual copies average families genome wide. Lastly, while old gradually lose entire lifespan, demethylation happens late life associated with cancer. negative consequences. Morandini et al. transposons peripheral mononuclear cells models transposon accurately predict age.

Language: Английский

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Épigénétique et cancer

médecine/sciences, Journal Year: 2024, Volume and Issue: 40(12), P. 925 - 934

Published: Dec. 1, 2024

Les altérations des profils de méthylation l’ADN sont retrouvées dans les cellules cancéreuses, combinant une hypométhylation globale du génome avec hyperméthylation régions spécifiques, telles que îlots CpG, normalement non méthylés. Des effets moteurs le développement cancer ont été associés à certaines modifiées par la l’ADN, induisant exemple répression gènes suppresseurs tumeur ou l’activation d’oncogènes et rétrotransposons. Ces représentent candidats premier plan pour marqueurs spécifiques détection, diagnostic pronostic cancer. En particulier, ces marqueurs, distribués long génome, mine d’informations qui offre perspectives d’innovation en biopsie liquide, notamment grâce l’émergence l’intelligence artificielle visée diagnostique. Ceci pourrait lever verrous liés aux sensibilités spécificités restent encore limitées applications plus difficiles oncologie : détection cancers un stade précoce, suivi maladie résiduelle l’analyse tumeurs cérébrales. Le ciblage processus enzymatiques contrôlent l’épigénome offrent outre nouvelles stratégies thérapeutiques pourraient remédier anomalies régulation épigénomes altérés.

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Non-invasive multi-cancer diagnosis using DNA hypomethylation of LINE-1 retrotransposons

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 23, 2024

Abstract Purpose The detection of circulating tumor DNA, which allows non-invasive molecular profiling and disease follow-up, promises optimal individualized management patients with cancer. However, detecting small fractions DNA released when the burden is reduced remains a challenge. Experimental Design We implemented new highly sensitive strategy to detect base-pair resolution methylation patterns from plasma assessed potential hypomethylation LINE-1 retrotransposons as multi-cancer biomarker. DIAMOND (Detection Long Interspersed Nuclear Element Altered Methylation ON DNA) method targets 30-40,000 young L1 scattered throughout genome, covering about 100,000 CpG sites based on reference-free analysis pipeline. Results Resulting machine learning-based classifiers showed powerful correct classification rates discriminating healthy plasmas 6 types cancers (colorectal, breast, lung, ovarian, gastric uveal melanoma including localized stages) in two independent cohorts (AUC = 88% 100%, N 747). can also be used perform copy number alterations (CNA) improves cancer detection. Conclusions This should lead development more efficient diagnostic tests adapted all patients, universality these factors. Statement significance assay (L1) DNA. It provided high coverage data using affordable sequencing depth, instrumental achieve sensitivity work minute amounts cell-free discrimination between

Language: Английский

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Every repeat is unique: Exploring the genomic impact of human L1 retrotransposons at locus-specific resolution

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(2), P. 100504 - 100504

Published: Feb. 1, 2024

Fully understanding the impact of human retrotransposon L1 requires that each ∼500,000 copies be evaluated as a potentially unique genomic entity. In this issue Cell Genomics, Lanciano et al.1 strive toward goal, illuminating reciprocal regulatory influence between individual L1s and their integration sites.

Language: Английский

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Technology to the rescue: how to uncover the role of transposable elements in preimplantation development

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(3), P. 1349 - 1362

Published: May 16, 2024

Transposable elements (TEs) are highly expressed in preimplantation development. Preimplantation development is the phase when cells of early embryo undergo first cell fate choice and change from being totipotent to pluripotent. A range studies have advanced our understanding TEs preimplantation, as well their epigenetic regulation functional roles. However, many questions remain about implications TE expression during Challenges originate due abundance genome, second because limited numbers preimplantation. Here we review most recent technological advancements promising shed light onto role We explore novel avenues identify genomic insertions improve regulatory mechanisms roles RNA protein products

Language: Английский

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DNA methylation protects cancer cells against non-canonical senescence

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 23, 2024

Abstract Inhibitors of DNA methylation such as 5-aza-deoxycytidine are widely used in experimental and clinical settings. However, their mechanism action is that damage inevitably co-occurs with loss methylation, making it challenging to discern respective effects. Here we deconvolute the effects decreased on cancer cells, by using degron alleles key regulators. We report cells —but no damage— enter cellular senescence, G1 arrest, SASP expression, SA-β-gal positivity. This senescence independent p53 Rb, but involves p21, which cytoplasmic inhibits apoptosis, cGAS, playing a STING-independent role nucleus. Xenograft experiments show tumor can be made senescent vivo decreasing methylation. These findings reveal intrinsic have practical implications for future therapeutic approaches.

Language: Английский

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Endogenous retroelements in hematological malignancies: From epigenetic dysregulation to therapeutic targeting

American Journal of Hematology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 10, 2024

Endogenous retroelements (EREs), which comprise half of the human genome, play a pivotal role in genome dynamics. Some EREs retained ability to encode proteins, although most degenerated or served as source for novel genes and regulatory elements during evolution. Despite ERE repression mechanisms developed maintain stability, widespread pervasive activation is observed cancer including hematological malignancies. Challenging perception noncoding DNA "junk," are underestimated contributors driver well antitumoral immunity by providing innate immune ligands tumor antigens. This review highlights recent progress understanding co-option events focuses on controversial debate surrounding their causal shaping malignant phenotype. We provide insights into rapidly evolving landscape research malignancies clinical implications these cancers.

Language: Английский

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