Age and sex effects on blood retrotransposable element expression levels: Findings from the population-based Rhineland Study DOI Creative Commons
Valentina Talevi, Hang‐Mao Lee, Dan Liu

et al.

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

Published: Dec. 17, 2024

Abstract Retrotransposable elements (RTEs) have been implicated in the pathogenesis of several age-associated diseases. Although model systems indicate that age- and sex-dependent loss heterochromatin increases RTE expression, data from large human studies are lacking. Here we assessed expression levels 795 blood subfamilies 2467 participants population-based Rhineland Study. We found more than 98% increased with both chronological biological age. Moreover, regulators involved silencing were negatively related to 690 subfamilies. Finally, observed sex differences 42 subfamilies, higher men. The genes mapped sex-related RTEs enriched immune response-related pathways. Importantly, validated our key findings an independent cohort. Our their repressors markers aging, dysregulation is linked inflammation, especially Graphical abstract

Language: Английский

How do lifestyle and environmental factors influence the sperm epigenome? Effects on sperm fertilising ability, embryo development, and offspring health DOI Creative Commons

Ayazhan Akhatova,

Céline Jones,

Kevin Coward

et al.

Clinical Epigenetics, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 16, 2025

Recent studies support the influence of paternal lifestyle and diet before conception on health offspring via epigenetic inheritance through sperm DNA methylation, histone modification, small non-coding RNA (sncRNA) expression regulation. Smoking may induce hypermethylation in genes related to anti-oxidation insulin resistance. Paternal obesity are associated with greater risks metabolic dysfunction alterations sperm. Metabolic changes, such as high blood glucose levels increased body weight, commonly observed fathers subjected chronic stress, addition an enhanced risk depressive-like behaviour sensitivity stress both F0 F1 generations. methylation is correlated quality ability fertilise oocytes, possibly a differentially regulated MAKP81IP3 signalling pathway. exposure toxic endocrine-disrupting chemicals (EDCs) also linked transgenerational transmission predisposition disease, infertility, testicular disorders, obesity, polycystic ovarian syndrome (PCOS) females changes during gametogenesis. As success assisted reproductive technology (ART) affected by diet, BMI, alcohol consumption, its outcomes could be improved modifying factors that dependent male choices environmental factors. This review discusses importance signatures sperm—including retention, sncRNA—for functionality, early embryo development, health. We discuss mechanisms which (obesity, smoking, EDCs, stress) impact epigenome.

Language: Английский

Citations

2
Epigenomic insights into common human disease pathology DOI Creative Commons
Christopher G. Bell

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: April 11, 2024

Abstract The epigenome—the chemical modifications and chromatin-related packaging of the genome—enables same genetic template to be activated or repressed in different cellular settings. This multi-layered mechanism facilitates cell-type specific function by setting local sequence 3D interactive activity level. Gene transcription is further modulated through interplay with factors co-regulators. human body requires this epigenomic apparatus precisely installed throughout development then adequately maintained during lifespan. causal role epigenome pathology, beyond imprinting disorders tumour suppressor genes, was brought into spotlight large-scale sequencing projects identifying that mutations machinery genes could critical drivers both cancer developmental disorders. Abrogation providing new molecular insights pathogenesis. However, deciphering full breadth implications these changes remains challenging. Knowledge accruing regarding disease mechanisms clinical biomarkers, pathogenically relevant surrogate tissue analyses, respectively. Advances include consortia generated reference epigenomes, high-throughput DNA methylome association studies, as well ageing-related diseases from biological ‘clocks’ constructed machine learning algorithms. Also, 3rd-generation beginning disentangle complexity modification haplotypes. Cell-free methylation a biomarker has clear utility potential assess organ damage across many Finally, understanding aetiology brings it opportunity for exact therapeutic alteration CRISPR-activation inhibition.

Language: Английский

Citations

10
LINE-1, the NORth star of nucleolar organization DOI Open Access
Misaki Matsuo, Gaël Cristofari

Genes & Development, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Long interspersed element-1 (LINE-1) retrotransposons are abundant transposable elements in mammals and significantly influence chromosome structure, chromatin organization, 3D genome architecture. In this issue of Genes & Development , Ataei et al. (doi:10.1101/gad.351979.124) identify a homininae-specific LINE-1 element within nucleolar ogranizer regions (NORs) that is specifically transcribed naïve human embryonic stem cells. Deletion or silencing disrupts organization function alters cellular identity. These findings provide novel insights into the role suggest individual may have evolved specialized roles.

Language: Английский

Citations

1
LINE-1 retrotransposons contribute to mouse PV interneuron development DOI Creative Commons
Gabriela O. Bodea,

Juan M. Botto,

Maria E. Ferreiro

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(7), P. 1274 - 1284

Published: May 21, 2024

Abstract Retrotransposons are mobile DNA sequences duplicated via transcription and reverse of an RNA intermediate. Cis -regulatory elements encoded by retrotransposons can also promote the adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons. It is, however, unclear whether L1 only some neuronal lineages or therein neurodevelopmental gene expression. Here we report programmed activation SOX6, a factor critical for parvalbumin (PV) interneuron development. Mouse PV interneurons permit mobilization vitro vivo, harbor unmethylated promoters express full-length mRNAs proteins. Using nanopore long-read sequencing, identify L1s proximal to genes, including novel promoter-driven Caps2 transcript isoform that enhances neuron morphological complexity vitro. These data highlight contribution made cis development transcriptome diversity, uncovered due mobility this milieu.

Language: Английский

Citations

8
Regulation and function of transposable elements in cancer genomes DOI Creative Commons
Michael Lee, Syed Farhan Ahmad, Jian Xu

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 31, 2024

Abstract Over half of human genomic DNA is composed repetitive sequences generated throughout evolution by prolific mobile genetic parasites called transposable elements (TEs). Long disregarded as “junk” or “selfish” DNA, TEs are increasingly recognized formative in genome evolution, wired intimately into the structure and function genome. Advances sequencing technologies computational methods have ushered an era unprecedented insight how TE activity impacts biology health disease. Here we discuss current views on shaped regulatory landscape genome, implicated cancers, recent findings motivate novel strategies to leverage for improved cancer therapy. Given crucial role methodological advances biology, pair our conceptual discussions with in-depth review inherent technical challenges studying repeats, specifically related structural variation, expression analyses, chromatin regulation. Lastly, provide a catalog existing emerging assays bioinformatic software that altogether enabling most sophisticated comprehensive investigations yet regulation interspersed repeats genomes.

Language: Английский

Citations

6
DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor DOI Creative Commons
Ninoslav Pandiloski, Vivien Horváth, Ofelia Karlsson

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 30, 2024

The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 effectors remodel chromatin. How HUSH operate alongside DNA methylation, a central epigenetic regulator repeat transcription, remains largely unknown. Here we interrogate this relationship in neural progenitor cells (hNPCs), somatic model brain development that tolerates removal methyltransferase DNMT1. Upon loss or subunit TASOR hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation activation evolutionarily-young attracts binding, simultaneous depletion DNMT1 causes massive accumulation L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites clustered protocadherin genes, repetitive elements important for chromosome structure neurodevelopment respectively. Our data delineate control repeats cells, with implications understanding vital functions HUSH-MORC2 hypomethylated contexts throughout development.

Language: Английский

Citations

5
An endogenous retroviral element co-opts an upstream regulatory sequence to achieve somatic expression and mobility DOI Creative Commons
Natalia Rubanova, Darshika Singh,

Louis Barolle

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Retrotransposons, multi-copy sequences that propagate via copy-and-paste mechanisms involving an RNA intermediate, occupy large portions of all eukaryotic genomes. A great majority their manifold copies remain silenced in somatic cells, nevertheless, some are transcribed, often a tissue specific manner, and small fraction retains its ability to mobilize. Retrotransposon expression or mobility increasingly recognized contribute normal development homeostasis, as well aging disease. While it is characterized retrotransposon may provide cis regulatory elements for neighboring genes, how own achieved different contexts not understood. Here, using long-read DNA sequencing, we characterize retrotransposition the Drosophila intestine. We show retroelement does change significantly upon limited very few active sub-families retrotransposons. Importantly, identify polymorphic donor locus endogenous LTR retroviral element rover , intestinal tissue. reveal gut activity copy depends on genomic environment. Without affecting local gene expression, co-opts upstream enhancer sequence, rich transcription factor binding sites, expression. Further escargot, snail-type critical progenitor cell function, can drive transcriptional copy. These data new insights into locus-specific features allow retrotransposons produce functional transcripts mobilize lineage.

Language: Английский

Citations

0
LINE-1 ORF1p expression occurs in clear cell ovarian carcinoma precursors and is a candidate blood biomarker DOI Creative Commons
Pamela Santiago, Sho Sato, Stephanie J. Zhang

et al.

npj Precision Oncology, Journal Year: 2025, Volume and Issue: 9(1)

Published: March 6, 2025

Long interspersed element 1 (LINE-1) retrotransposons are repetitive sequences that can move within the genome by an autonomous mechanism. To limit their mutagenic potential, benign cells restrict LINE-1 expression through molecular mechanisms such as DNA methylation and histone modification, but these usually impaired in cancer. Clear cell ovarian carcinoma (CCOC) represents 5-10% of cancers is thought to arise from endometriosis. Women with advanced CCOC face poor prognoses, highlighting importance understanding early disease pathogenesis. In our study, 33 40 cases (over 82%) tumors express ORF1p, a LINE-1-encoded protein. We found de-repression event CCOC, ORF1p enhanced during transition typical atypical endometriosis persists invasive Finally, using single-molecule array (Simoa) assays, we detected patient blood, suggesting it potential minimally biomarker for this disease.

Language: Английский

Citations

0
Intermittent fasting attenuates CNS inflammaging - rebalancing the transposonome DOI Creative Commons
Mitchell J Cummins, Ethan T Cresswell, Doug W. Smith

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Abstract A hallmark of CNS aging is sterile, chronic, low-grade neuroinflammation. Understanding how the develops chronic inflammation necessary to achieve extended healthspan. Characterisation neuroinflammatory molecular triggers remains limited. Interventions that reduce neuroinflammation and extend health lifespan could be useful in this regard. One such intervention intermittent fasting (IF), but IF impacts insufficiently understood. To address this, we performed deep RNA-sequencing on young, middle-aged, old, mouse regions. Additionally, sequenced spinal cord animals subject adult lifelong IF. We found most differentially expressed genes (DEGs) at middle age were region specific (~ 50–84%), whilst effect weakened 18–72%) old age, suggesting emergence a more general global profile. DEGs from all regions enriched for inflammatory immune ontologies. Surprisingly, SC was aging- neuroinflammation-impacted both ages, with by far highest number DEGs, largest net increase expression transposable elements (TEs), greatest enrichment immune-related ontologies, generally larger increases gene expression. Overall, normal upregulation sensors non-self, DNA/RNA, activation inflammasomes, cGAS-STING1 interferon response genes, across CNS. Whilst still developed an profile SC, average lower ~ 50% compared age-matched controls. IF-specific apparent, also acts separate, potentially targetable, pathways those impacted aging. Expression disease associated microglia, phagocytic exhaustion, STING1, inflammasome decreased Significantly, TE reversed decrease. In summary, find hotspot, attenuates neuroinflammaging rebalancing transposonome.

Language: Английский

Citations

0
Age and Sex Effects on Blood Retrotransposable Element Expression Levels: Findings From the Population‐Based Rhineland Study DOI Creative Commons
Valentina Talevi, Hang‐Mao Lee, Dan Liu

et al.

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

ABSTRACT Retrotransposable elements (RTEs) have been implicated in the pathogenesis of several age‐associated diseases. Although model systems indicate that age‐ and sex‐dependent loss heterochromatin increases RTE expression, data from large human studies are lacking. Here we assessed expression levels 795 blood subfamilies 2467 participants population‐based Rhineland Study. We found more than 98% increased with both chronological biological age. Moreover, regulators involved silencing was negatively related to 690 subfamilies. Finally, observed sex differences 42 subfamilies, higher men. The genes mapped sex‐related RTEs were enriched immune response‐related pathways. Importantly, validated our key findings an independent cohort. Our their repressors markers aging dysregulation is linked inflammation, especially

Language: Английский

Citations

0