Regulation of human trophoblast gene expression by endogenous retroviruses

Nature Structural & Molecular Biology, Год журнала: 2023, Номер 30(4), С. 527 - 538

Опубликована: Апрель 1, 2023

The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate variation affect host gene regulation, may helped define species-specific trophoblast expression programs. Here we assess contribution of transposable elements human as enhancers or promoters. Using epigenomic data from primary stem-cell lines, identified multiple endogenous retrovirus families regulatory potential that lie close genes preferential in trophoblast. These largely primate-specific are associated inter-species bound by transcription factors key roles development. editing, demonstrate several act transcriptional important genes, such CSF1R PSG5. We also identify an LTR10A element regulates ENG expression, affecting secretion soluble endoglin, implications for preeclampsia. Our show transposons made contributions suggest activity pregnancy outcomes.

Язык: Английский

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Recurrent oncogenic ZC3H18 mutations stabilize endogenous retroviral RNA

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

Опубликована: Янв. 14, 2025

Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. We found that ZC3H18 (Z18), a component of multiple nuclear surveillance complexes, has recurrent truncating mutations cancer. show Z18 trunc are oncogenic plays an evolutionarily conserved role ERV RNA. In zebrafish, expedited melanoma onset promoted specific accumulation mutant human cell lines from Cancer Cell Line Encyclopedia also higher levels engineered cells, enhanced more than loss one copy, indicating dominant negative activity. directly bound stabilized Notably, expression was sufficient to expedite oncogenesis zebrafish model, which first evidence we aware transcripts can play functional Our work illuminates mechanism for elevated cancer supports aberrant broadly oncogenic.

Язык: Английский

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Multi-tissue transcriptomic characterization of endogenous retrovirus-derived transcripts in Capra hircus

Frontiers in Genetics, Год журнала: 2025, Номер 16

Опубликована: Март 19, 2025

Background Transposable elements (TEs, or transposons) are repetitive genomic sequences, accounting for half of a mammal genome. Most TEs transcriptionally silenced, whereas some TEs, especially endogenous retroviruses (ERVs, long terminal repeat retrotransposons), physiologically expressed in certain conditions. However, the expression pattern those less studied species, like goat ( Capra hircus ), remains unclear. To obtain an overview and transcriptomic features ERVs goat, important farm we herein analyzed transcriptomes ten C. tissues cells under various physiological pathological Method Distribution classes, families, subfamilies genome were systematically annotated. The patterns TE-derived transcripts multiple investigated at subfamily location levels. Differential ERV-derived reads was measured conditions, such as embryo development virus infection challenges. Co-expression between ERV-reads their proximal genes also explored to decipher regulation transcripts. Results There around 800 TE genome, 49.1% sequence. account 10% transcriptome abundance comparable tissues, while variable among tissues. We further characterized ERV analysis showed that highly active 16-cell embryos, when zygote begins transcribe its own genes. recognized numerous activated response RNA lung, spleen, caecum, immune cells. CapAeg_1.233:ERVK chromosome 1 17 dysregulated endometrium They strong co-expression with gene OAS1 TMPRSS2 , indicating impact on nearby ERVs. Conclusion generated across identified different

Язык: Английский

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Identification of FLYWCH1 as a regulator of platinum-resistance in epithelial ovarian cancer.

PubMed, Год журнала: 2025, Номер 7(2), С. zcaf012 - zcaf012

Опубликована: Июнь 1, 2025

Platinum-based combination chemotherapy remains the backbone of first-line treatment for patients with advanced epithelial ovarian cancer (EOC). While most initially respond well to treatment, relapse ultimately develop platinum resistance. This study identified FLYWCH-type zinc finger-containing protein 1 (FLYWCH1) as an important regulator in resistance development process. We showed that loss FLYWCH1 promotes EOC cells, and low expression is correlated poor prognosis patients. In platinum-sensitive colocalizes H3K9me3, but this association significantly reduced when cells acquire The suppression induces gene changes resulting deregulation pathways associated line its connection silencing a synthetic reporter assay alters H3K9me3 at promoter regions repeat elements. leads derepression LTR Alu repeats, thereby increasing transcriptional plasticity driving Our data highlight importance chromatin biology acquisition through propose potential biomarker predicting responses

Язык: Английский

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Cancer cells’ chamber of secrets: the link between micronuclei, chromothripsis and malignancy

Open Biology, Год журнала: 2025, Номер 15(5)

Опубликована: Май 1, 2025

Micronuclei exhibit defective proteomes rendering their chromatin vulnerable to fragmentation. This fragmentation process, known as chromothripsis, promotes tumorigenesis by catalysing the activation of oncogenes and silencing tumor suppressors. With this role in mind, micronuclei serve promising targets for therapeutic intervention. review will explore recent discoveries regarding how form, function chromothripsis provides a selective advantage cancer cells.

Язык: Английский

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An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140

Human Molecular Genetics, Год журнала: 2024, Номер 33(16), С. 1454 - 1464

Опубликована: Май 15, 2024

Speckled Protein 140 (SP140) is a chromatin reader with critical roles regulating immune cell transcriptional programs, and SP140 splice variants are associated diseases including Crohn's disease, multiple sclerosis, chronic lymphocytic leukemia. expression currently thought to be restricted cells. However, by analyzing human transcriptomic datasets from wide range of normal cancer types, we found recurrent cancer-specific SP140, driven an alternative intronic promoter derived endogenous retrovirus (ERV). The ERV belongs the primate-specific LTR8B family regulated oncogenic mitogen-activated protein kinase (MAPK) signaling. drives isoforms, nearly full-length isoform that retains all functional domains canonical also localized within nucleus, consistent role in regulation. In fibrosarcoma line, silencing resulted increased sensitivity interferon-mediated cytotoxicity dysregulation genes. Our findings implicate aberrant ERV-mediated as novel mechanism contributing gene

Язык: Английский

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Dual roles of human endogenous retroviruses in cancer progression and antitumor immune response

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2024, Номер 1879(6), С. 189201 - 189201

Опубликована: Окт. 18, 2024

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 12, 2023

Less than 0.5% of people living with HIV-1 are elite controllers (ECs) - individuals who have a replication-competent viral reservoir in their CD4

Язык: Английский

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The RNA Revolution in the Central Molecular Biology Dogma Evolution

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(23), С. 12695 - 12695

Опубликована: Ноя. 26, 2024

Human genome projects in the 1990s identified about 20,000 protein-coding sequences. We are now RNA revolution, propelled by realization that genes determine phenotype beyond foundational central molecular biology dogma, stating inherited linear pieces of DNA transcribed to RNAs and translated into proteins. Crucially, over 95% genome, initially considered junk between genes, encodes essential, functionally diverse non-protein-coding RNAs, raising gene count at least one order magnitude. Most phenotype-determining changes regulatory areas control can directly or indirectly phenotypes regulating protein function, transferring information within organisms, generating DNA. also exhibit high structural, functional, biomolecular interaction plasticity modified via editing, methylation, glycosylation, other mechanisms, which bestow them with intra- extracellular functions without altering underlying is, therefore, currently primary determinant cellular populational functional diversity, disease-linked structural variations, cell function regulation. As demonstrated RNA-based coronavirus vaccines' success, technology is transforming medicine, agriculture, industry, as did advent recombinant 1980s.

Язык: Английский

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Histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(52)

Опубликована: Дек. 17, 2024

The H3K9me3-specific histone methyltransferase SETDB1 is critical for proper regulation of developmental processes, but the underlying mechanisms are only partially understood. Here, we show that deletion Setdb1 in mouse fetal liver hematopoietic stem and progenitor cells (HSPCs) results compromised cell function, enhanced myeloerythroid differentiation, impaired lymphoid development. Notably, -deficient HSPCs exhibit reduced quiescence increased proliferation, accompanied by acquisition a lineage-biased transcriptional program. In HSPCs, identify genomic regions characterized loss H3K9me3 chromatin accessibility, suggesting transcription factor (TF) activity. Interestingly, TFs like PU.1 bind these cryptic enhancers wild-type despite status. Thus, our data indicate restricts activation nonphysiological TF binding sites which helps to ensure maintenance differentiation HSPCs.

Язык: Английский

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