Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.481
Filtrar
1.
Environ Mol Mutagen ; 63(6): 275-285, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36054626

RESUMO

Bisphenol A (BPA), a recognized endocrine-disrupting chemical, is used in the production of epoxy and polycarbonate resins. Since human exposure to BPA has been associated with increased cancer susceptibility, the market has shifted to products often labeled as "BPA free" containing BPA analogs such as bisphenol F (BPF) and bisphenol S (BPS). However, the European legislation on BPF and BPS is still unclear. This study analyzed the effects of BPA, BPF, and BPS exposure on human peripheral blood mononuclear cells by using in vitro micronucleus assay. Furthermore, it investigated the impact of bisphenols exposure on human endogenous retroviruses (HERVs) expression, which is implicated with the pathogenesis of several human diseases. The micronucleus assay revealed a significant genotoxic effect in peripheral blood cells after exposure to BPA and BPF at concentrations of 0.1, 0.05, and 0.025 µg/ml, and to BPS at 0.1 and 0.05 µg/ml. In addition, BPA exposure seems to upregulate the expression of HERVs, while a downregulation was observed after BPF and BPS treatments. Overall, our data showed the toxic effect of BPA and its analogs on circulating cells in the blood and demonstrated that they could modulate the HERVs expression.


Assuntos
Retrovirus Endógenos , Compostos Benzidrílicos/toxicidade , Genômica , Humanos , Leucócitos Mononucleares , Fenóis , Sulfonas
2.
Nat Commun ; 13(1): 5447, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123357

RESUMO

Silencing of endogenous retroviruses (ERVs) is largely mediated by repressive chromatin modifications H3K9me3 and DNA methylation. On ERVs, these modifications are mainly deposited by the histone methyltransferase Setdb1 and by the maintenance DNA methyltransferase Dnmt1. Knock-out of either Setdb1 or Dnmt1 leads to ERV de-repression in various cell types. However, it is currently not known if H3K9me3 and DNA methylation depend on each other for ERV silencing. Here we show that conditional knock-out of Setdb1 in mouse embryonic endoderm results in ERV de-repression in visceral endoderm (VE) descendants and does not occur in definitive endoderm (DE). Deletion of Setdb1 in VE progenitors results in loss of H3K9me3 and reduced DNA methylation of Intracisternal A-particle (IAP) elements, consistent with up-regulation of this ERV family. In DE, loss of Setdb1 does not affect H3K9me3 nor DNA methylation, suggesting Setdb1-independent pathways for maintaining these modifications. Importantly, Dnmt1 knock-out results in IAP de-repression in both visceral and definitive endoderm cells, while H3K9me3 is unaltered. Thus, our data suggest a dominant role of DNA methylation over H3K9me3 for IAP silencing in endoderm cells. Our findings suggest that Setdb1-meditated H3K9me3 is not sufficient for IAP silencing, but rather critical for maintaining high DNA methylation.


Assuntos
Metilação de DNA , Retrovirus Endógenos , Animais , Cromatina/metabolismo , DNA/metabolismo , Endoderma/metabolismo , Retrovirus Endógenos/metabolismo , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Camundongos
3.
Int J Mol Sci ; 23(17)2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36077510

RESUMO

Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases.


Assuntos
Retrovirus Endógenos , Infecções por Retroviridae , Retrovirus Endógenos/genética , Epigênese Genética , Genoma Humano , Humanos , Infecções por Retroviridae/genética
4.
Cells ; 11(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35954237

RESUMO

About half of the mammalian genome is constituted of repeated elements, among which endogenous retroviruses (ERVs) are known to influence gene expression and cancer development. The HP1 (Heterochromatin Protein 1) proteins are known to be essential for heterochromatin establishment and function and its loss in hepatocytes leads to the reactivation of specific ERVs and to liver tumorigenesis. Here, by studying two ERVs located upstream of genes upregulated upon loss of HP1, Mbd1 and Trim24, we show that these HP1-dependent ERVs behave as either alternative promoters or as putative enhancers forming a loop with promoters of endogenous genes depending on the genomic context and HP1 expression level. These ERVs are characterised by a specific HP1-independent enrichment in heterochromatin-associated marks H3K9me3 and H4K20me3 as well as in the enhancer-specific mark H3K4me1, a combination that might represent a bookmark of putative ERV-derived enhancers. These ERVs are further enriched in a HP1-dependent manner in H3K27me3, suggesting a critical role of this mark together with HP1 in the silencing of the ERVs, as well as for the repression of the associated genes. Altogether, these results lead to the identification of a new regulatory hub involving the HP1-dependent formation of a physical loop between specific ERVs and endogenous genes.


Assuntos
Retrovirus Endógenos , Animais , Cromatina/genética , Homólogo 5 da Proteína Cromobox , Retrovirus Endógenos/genética , Expressão Gênica , Heterocromatina , Mamíferos/genética
5.
Cells ; 11(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35954303

RESUMO

The main roles of placentas include physical protection, nutrient and oxygen import, export of gasses and fetal waste products, and endocrinological regulation. In addition to physical protection of the fetus, the placentas must provide immune protection throughout gestation. These basic functions are well-conserved; however, placentas are undoubtedly recent evolving organs with structural and cellular diversities. These differences have been explained for the last two decades through co-opting genes and gene control elements derived from transposable elements, including endogenous retroviruses (ERVs). However, the differences in placental structures have not been explained or characterized. This manuscript addresses the sorting of ERVs and their integration into the mammalian genomes and provides new ways to explain why placental structures have diverged.


Assuntos
Retrovirus Endógenos , Animais , Elementos de DNA Transponíveis , Retrovirus Endógenos/genética , Feminino , Mamíferos/genética , Placenta , Gravidez
6.
Int J Mol Sci ; 23(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35955468

RESUMO

The triggers for the development of multiple sclerosis (MS) have not been fully understood to date. One hypothesis proposes a viral etiology. Interestingly, viral proteins from human endogenous retroviruses (HERVs) may play a role in the pathogenesis of MS. Allelic variants of the HERV-K18 env gene represent a genetic risk factor for MS, and the envelope protein is considered to be an Epstein-Barr virus-trans-activated superantigen. To further specify a possible role for HERV-K18 in MS, the present study examined the immunogenicity of the purified surface unit (SU). HERV-K18(SU) induced envelope-specific plasma IgG in immunized mice and triggered proliferation of T cells isolated from these mice. It did not trigger phenotypic changes in a mouse model of experimental autoimmune encephalomyelitis. Further studies are needed to investigate the underlying mechanisms of HERV-K18 interaction with immune system regulators in more detail.


Assuntos
Retrovirus Endógenos , Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Animais , Retrovirus Endógenos/genética , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Humanos , Melfalan , Camundongos , gama-Globulinas
7.
Mol Cells ; 45(8): 522-530, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-35950452

RESUMO

Transposable elements (TEs) account for approximately 45% of the human genome. TEs have proliferated randomly and integrated into functional genes during hominoid radiation. They appear as right-handed B-DNA double helices and slightly elongated left-handed Z-DNAs. Human endogenous retrovirus (HERV) families are widely distributed in human chromosomes at a ratio of 8%. They contain a 5'-long terminal repeat (LTR)-gag-pol-env-3'-LTR structure. LTRs contain the U3 enhancer and promoter region, transcribed R region, and U5 region. LTRs can influence host gene expression by acting as regulatory elements. In this review, we describe the alternative promoters derived from LTR elements that overlap Z-DNA by comparing Z-hunt and DeepZ data for human functional genes. We also present evidence showing the regulatory activity of LTR elements containing Z-DNA in GSDML. Taken together, the regulatory activity of LTR elements with Z-DNA allows us to understand gene function in relation to various human diseases.


Assuntos
DNA Forma Z , Retrovirus Endógenos , Retrovirus Endógenos/genética , Humanos , Regiões Promotoras Genéticas/genética , Sequências Repetidas Terminais/genética
8.
Cells ; 11(16)2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36010599

RESUMO

Repetitive sequences represent about half of the human genome. They are actively transcribed and play a role during development and in epigenetic regulation. The altered activity of repetitive sequences can lead to genomic instability and they can contribute to the establishment or the progression of degenerative diseases and cancer transformation. In this work, we analyzed the expression profiles of DNA repetitive sequences in the breast cancer specimens of the HMUCC cohort. Satellite expression is generally upregulated in breast cancers, with specific families upregulated per histotype: in HER2-enriched cancers, they are the human satellite II (HSATII), in luminal A and B, they are part of the ALR family and in triple-negative, they are part of SAR and GSAT families, together with a perturbation in the transcription from endogenous retroviruses and their LTR sequences. We report that the background expression of repetitive sequences in healthy tissues of cancer patients differs from the tissues of non-cancerous controls. To conclude, peculiar patterns of expression of repetitive sequences are reported in each specimen, especially in the case of transcripts arising from satellite repeats.


Assuntos
Neoplasias da Mama , Retrovirus Endógenos , Neoplasias da Mama/genética , Retrovirus Endógenos/genética , Epigênese Genética , Feminino , Genoma Humano , Humanos , Sequências Repetitivas de Ácido Nucleico/genética
9.
Proc Natl Acad Sci U S A ; 119(33): e2122680119, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35943984

RESUMO

Koala retrovirus (KoRV) subtype A (KoRV-A) is currently in transition from exogenous virus to endogenous viral element, providing an ideal system to elucidate retroviral-host coevolution. We characterized KoRV geography using fecal DNA from 192 samples across 20 populations throughout the koala's range. We reveal an abrupt change in KoRV genetics and incidence at the Victoria/New South Wales state border. In northern koalas, pol gene copies were ubiquitously present at above five per cell, consistent with endogenous KoRV. In southern koalas, pol copies were detected in only 25.8% of koalas and always at copy numbers below one, while the env gene was detected in all animals and in a majority at copy numbers above one per cell. These results suggest that southern koalas carry partial endogenous KoRV-like sequences. Deep sequencing of the env hypervariable region revealed three putatively endogenous KoRV-A sequences in northern koalas and a single, distinct sequence present in all southern koalas. Among northern populations, env sequence diversity decreased with distance from the equator, suggesting infectious KoRV-A invaded the koala genome in northern Australia and then spread south. The exogenous KoRV subtypes (B to K), two novel subtypes, and intermediate subtypes were detected in all northern koala populations but were strikingly absent from all southern animals tested. Apart from KoRV subtype D, these exogenous subtypes were generally locally prevalent but geographically restricted, producing KoRV genetic differentiation among northern populations. This suggests that sporadic evolution and local transmission of the exogenous subtypes have occurred within northern Australia, but this has not extended into animals within southern Australia.


Assuntos
Retrovirus Endógenos , Evolução Molecular , Gammaretrovirus , Phascolarctidae , Animais , Retrovirus Endógenos/genética , Gammaretrovirus/genética , Variação Genética , New South Wales , Phascolarctidae/virologia , Infecções por Retroviridae/transmissão , Infecções por Retroviridae/veterinária , Infecções por Retroviridae/virologia , Vitória
10.
Microbiol Spectr ; 10(4): e0128022, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-35852349

RESUMO

In this work, we observed an increased presence of antibodies (Abs) against type I interferon (IFN-I) in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care unit (ICU) compared to non-ICU COVID-19 patients and healthy control (HC) subjects. Human endogenous retrovirus W (HERV-W) can reactivate after viral infection; therefore, we also investigated the presence of antibodies against HERV-W envelope (HERV-W-env)-derived epitopes. A total of 113 subjects (41 female and 72 male subjects) were analyzed. A significant difference in autoantibodies against IFN-α, IFN-ω, and HERV-W was observed between HCs and ICU patients; indeed, the latter have higher levels of autoantibodies against IFN-α, IFN-ω, and HERV-W than subjects with mild COVID-19 and HCs. Neutralizing anti-IFN-I autoantibodies may affect the ability of IFN-I to bind to the type I interferon receptor (IFNAR), blocking the activation of the antiviral response. IMPORTANCE In this work, we report the increased presence of IFN autoantibodies in correlation with HERV-W-env autoantibodies in ICU COVID-19 patients. The novelty of the results is in the association of these IFN autoantibodies with autoantibodies against HERV-W-env, a protein recently discovered to be overexpressed in lymphocytes of COVID-19 patients and correlated with severe disease and pneumonia. Type I IFNs are part of a complex cross-regulatory network; however, in a small percentage of cases, the increase in autoantibodies against these proteins may lead to damage to the host instead of protection against infectious diseases.


Assuntos
COVID-19 , Retrovirus Endógenos , Interferon Tipo I , Autoanticorpos , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino
11.
Ann Neurol ; 92(4): 545-561, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35801347

RESUMO

OBJECTIVE: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env. METHODS: Env neurotoxicity was detected in ALS cerebrospinal fluid and confirmed using recombinant Env protein in a cell-based assay and a mouse model. The mechanism of neurotoxicity was assessed with immunoprecipitation followed by mass spectrometry and Western blot, and by screening a panel of inhibitors. RESULTS: We observed that recombinant HML-2 Env protein caused neurotoxicity resulting in neuronal cell death, retraction of neurites, and decreased neuronal electrical activity. Injection of the Env protein into the brains of mice also resulted in neuronal cell death. HML-2 Env protein was also found in the cerebrospinal fluid of patients with sporadic ALS. The neurotoxic properties of the Env and the cerebrospinal fluid could be rescued with the anti-Env antibody. The Env was found to bind to CD98HC complexed to ß1 integrin on the neuronal cell surface. Using a panel of compounds to screen for their ability to block Env-induced neurotoxicity, we found that several compounds were protective and are linked to the ß1 integrin pathway. INTERPRETATION: HERV-K Env is released extracellularly in ALS and causes neurotoxicity via a novel mechanism. Present results pave the way for new treatment strategies in sporadic ALS. ANN NEUROL 2022;92:545-561.


Assuntos
Esclerose Amiotrófica Lateral , Retrovirus Endógenos , Esclerose Amiotrófica Lateral/genética , Animais , Produtos do Gene env , Humanos , Integrina beta1 , Camundongos , Camundongos Transgênicos
13.
Nat Genet ; 54(8): 1238-1247, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35864192

RESUMO

Most endogenous retroviruses (ERVs) in mammals are incapable of retrotransposition; therefore, why ERV derepression is associated with lethality during early development has been a mystery. Here, we report that rapid and selective degradation of the heterochromatin adapter protein TRIM28 triggers dissociation of transcriptional condensates from loci encoding super-enhancer (SE)-driven pluripotency genes and their association with transcribed ERV loci in murine embryonic stem cells. Knockdown of ERV RNAs or forced expression of SE-enriched transcription factors rescued condensate localization at SEs in TRIM28-degraded cells. In a biochemical reconstitution system, ERV RNA facilitated partitioning of RNA polymerase II and the Mediator coactivator into phase-separated droplets. In TRIM28 knockout mouse embryos, single-cell RNA-seq analysis revealed specific depletion of pluripotent lineages. We propose that coding and noncoding nascent RNAs, including those produced by retrotransposons, may facilitate 'hijacking' of transcriptional condensates in various developmental and disease contexts.


Assuntos
Retrovirus Endógenos , Animais , Células-Tronco Embrionárias , Retrovirus Endógenos/genética , Heterocromatina , Mamíferos/genética , Camundongos , Corpos Nucleares , Retroelementos
14.
Nucleic Acids Res ; 50(13): 7326-7349, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35776115

RESUMO

SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene 'islands' that drive differentiation to other lineages. The 'unearthing' of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.


Assuntos
Retrovirus Endógenos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Retrovirus Endógenos/metabolismo , Genômica , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Camundongos
15.
Placenta ; 126: 150-159, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35816776

RESUMO

INTRODUCTION: Throughout human pregnancy there is a delicate balance between the maintenance of a proliferative, trophoblast stem cell pool (TSC) and the differentiation from TSC to placental cell sub-lineages like the syncytiotrophoblast (STB). The STB is comprised of multinucleated cells that come into direct contact with maternal blood and provides the first line of defense to protect the fetus from maternal infections. The differentiation of TSC towards STB is primarily driven by human endogenous retroviruses (HERV), specifically Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1). Beyond cell fusion, there is also evidence to suggest they can regulate cell proliferation and an antiviral response in other cell types. Therefore, we hypothesized that HERV can regulate cell proliferation as well as an antiviral response in TSCs. METHOD: shRNA was used to knockdown ERVW-1 in TSCs and revealed reduction in cell proliferation, differentiation, and cell fusion. RT-qPCR and flow cytometry was used to measure other HERV and the presence of Type I and Type II interferon receptors. RESULTS: ERVW-1 knockdown (KD) TSCs had a significantly longer cell doubling time and reduced expression of the proliferation marker Ki67. ERVW-1 KD cells also demonstrated a marked deficiency in the ability to differentiate. Interestingly, ERVFRD-1 was upregulated in both ERVW-1 KD TSC and STB cells compared to controls. Finally, we found that the Type I interferon receptors, IFNAR1 and IFNAR2 were significantly increased in ERVW-1 KD STB cells. DISCUSSION: These findings uncover critical HERV functions in the trophoblasts and a novel role for ERVW-1 during early human placental development.


Assuntos
Retrovirus Endógenos , Trofoblastos , Antivirais , Proliferação de Células , Retrovirus Endógenos/genética , Feminino , Produtos do Gene env , Humanos , Placenta/metabolismo , Gravidez , Proteínas da Gravidez , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Trofoblastos/metabolismo
16.
Nucleic Acids Res ; 50(15): 8491-8511, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35904814

RESUMO

DNA methylation (5-methylcytosine (5mC)) is critical for genome stability and transcriptional regulation in mammals. The discovery that ten-eleven translocation (TET) proteins catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized our perspective on the complexity and regulation of DNA modifications. However, to what extent the regulatory functions of TET1 can be attributed to its catalytic activity remains unclear. Here, we use genome engineering and quantitative multi-omics approaches to dissect the precise catalytic vs. non-catalytic functions of TET1 in murine embryonic stem cells (mESCs). Our study identifies TET1 as an essential interaction hub for multiple chromatin modifying complexes and a global regulator of histone modifications. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. In particular, we show that TET1 is critical for the establishment of H3K9me3 and H4K20me3 at endogenous retroviral elements (ERVs) and their silencing that is independent of its canonical role in DNA demethylation. Furthermore, we provide evidence that this repression of ERVs depends on the interaction between TET1 and SIN3A. In summary, we demonstrate that the non-catalytic functions of TET1 are critical for regulation of gene expression and the silencing of endogenous retroviruses in mESCs.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Retrovirus Endógenos , Proteínas Proto-Oncogênicas/metabolismo , 5-Metilcitosina/metabolismo , Animais , Citosina/metabolismo , Desmetilação do DNA , Metilação de DNA , Proteínas de Ligação a DNA/genética , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Expressão Gênica , Mamíferos/genética , Camundongos , Proteínas Proto-Oncogênicas/genética
17.
Microbiol Spectr ; 10(4): e0048522, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-35867400

RESUMO

The long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) are distributed throughout the human genome and provide favorable conditions to regulate the expression of their adjacent genes. HML-2 is the most biologically active subgroup of the HERV-K family, and expression of its members has been associated with many cancer types. The LTRs of HML-2 have been classified into three subgroups (LTR5A, LTR5B, and LTR5Hs) based on phylogenetic analyses. The current study aimed to explore the LTR transcriptional activity differences among the three subtypes and further explore the underlying factors. A total of 43 LTR5A elements, 62 LTR5B elements, and 194 LTR5Hs elements were selected. A phylogenetic tree showed that the LTR5Hs group was clearly separated from the LTR5A and LTR5B groups. A luciferase reporter assay indicated that LTR5Hs had the strongest promoter activity, followed by LTR5A and LTR5B. To investigate the underlying factors, LTR5Hs was divided into 4 sections, and the homologous fragments in LTR5B were replaced successively. Replacement of the third section (-263 to 0) significantly increased LTR5B activity. Subsequent mutation experiments revealed that the increased transcriptional activity was induced by the TATA box and the two p53 binding sites within the section. Further interference with TP53 significantly decreased LTR5Hs transcriptional activity. Chromatin immunoprecipitation (ChIP) and CUT&Tag experiments finally confirmed the direct binding of the p53 protein with the two LTR5Hs p53 binding sites. Overall, the two p53 binding sites in the third section (-263 to 0) of LTR5Hs were revealed to play critical roles in the difference in transcriptional activity among the three subtypes. IMPORTANCE Human endogenous retroviruses (HERVs) were integrated into the human genome in ancient times and have been coevolving with the host. Since the Human Genome Project, HERVs have attracted increasing attention. Many studies have focused on their characterization, evolution, and biological function. In particular, the expression of HERV-K has been associated with many diseases, such as germ cell tumors, neurotoxicity, ovarian cancer, prostate cancer, and melanoma. Indeed, two HML-2-produced proteins, Np9 and Rec, are associated with certain cancers. However, their roles in these disease associations remain unclear. The current work focused on subgroup HML-2 of HERV-K, which is recognized as the most biologically active subgroup, and aimed to explore the mechanistic basis of transcriptional activity. The results revealed that p53 deeply determined the activity of HML-2 LTR5Hs. p53 is a rather important tumor suppressor protein. It can regulate the expression of genes related to cell cycle arrest, organic processes, and apoptosis in response to cellular stress and is critical for the control of homeostasis. Previous ChIP and expression studies of individual genes suggested that p53 sites in HERV LTRs may be part of the p53 transcription program and directly regulate p53 target genes in a species-specific manner. However, the exact function of p53 in the regulation of HERV LTR expression is largely elusive. Our results clearly demonstrated the interaction between LTR5Hs of HML-2 and p53. They are of great significance for the future comprehensive study of the physiological and pathological functions of LTRs of HERVs.


Assuntos
Retrovirus Endógenos , Sítios de Ligação , Retrovirus Endógenos/genética , Humanos , Masculino , Filogenia , Sequências Repetidas Terminais , Proteína Supressora de Tumor p53/genética
18.
Genes Genomics ; 44(9): 1091-1097, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35802343

RESUMO

BACKGROUND: Among various human endogenous retroviruses (HERVs), the HERV-K (HML-2) group has been reported to be highly related to cancer. In pancreatic cancer cells, shRNA-mediated downregulation of HERV-K env RNA decreases cell proliferation and tumor growth through the RAS-ERK-RSK pathway; in colorectal cancer, CRISPR-Cas9 knockout (KO) of the HERV-K env gene affects tumorigenic characteristics through the nupr-1 gene. OBJECTIVE: The effect of HERV-K env KO has not been studied in ovarian cancer cell lines. In this study, we analyzed the tumorigenic characteristics of ovarian cancer cell lines, including cell proliferation, migration, and invasion, and the expression patterns of related proteins after CRISPR-Cas9 KO of the HERV-K env gene. METHODS: The HERV-K env gene KO was achieved using the CRISPR-Cas9 system in ovarian cancer cell lines SKOV3 and OVCAR3. Tumorigenic characteristics including cell proliferation, migration, and invasion were analyzed, and related protein expression was investigated by western blot analysis. RESULTS: The expression of the HERV-K env gene in KO cells was significantly reduced at RNA and protein levels, and tumorigenic characteristics including cell proliferation, migration, and invasion were significantly reduced. In HERV-K env KO SKOV3 cells, the expression of the RB protein was significantly up-regulated and the cyclin B1 protein level was significantly reduced. In contrast, in HERV-K env KO OVCAR3 cells, the level of phospho-RB protein was significantly reduced, but other protein levels were not changed. CONCLUSION: The results of this study showed that HERV-K env gene KO affects cell proliferation, invasion, and migration of ovarian cells through RB and Cyclin B1 proteins, but the specific regulation pattern can differ by cell line.


Assuntos
Retrovirus Endógenos , Neoplasias Ovarianas , Apoptose , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Retrovirus Endógenos/genética , Feminino , Técnicas de Inativação de Genes , Genes env , Humanos , Neoplasias Ovarianas/genética , RNA Interferente Pequeno , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
19.
Viruses ; 14(7)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35891351

RESUMO

Human endogenous retroviruses (HERVs) are viral "fossils" in the human genome that originated from the ancient integration of exogenous retroviruses. Although HERVs have sporadically been reported in nonhuman primate genomes, their deep origination in pan-primates remains to be explored. Hence, based on the in silico genomic mining of full-length HERVs in 49 primates, we performed the largest systematic survey to date of the distribution, phylogeny, and functional predictions of HERVs. Most importantly, we obtained conclusive evidence of nonhuman origin for most contemporary HERVs. We found that various supergroups, including HERVW9, HUERSP, HSERVIII, HERVIPADP, HERVK, and HERVHF, were widely distributed in Strepsirrhini, Platyrrhini (New World monkeys) and Catarrhini (Old World monkeys and apes). We found that numerous HERVHFs are spread by vertical transmission within Catarrhini and one HERVHF was traced in 17 species, indicating its ancient nature. We also discovered that 164 HERVs were likely involved in genomic rearrangement and 107 HERVs were potentially coopted in the form of noncoding RNAs (ncRNAs) in humans. In summary, we provided comprehensive data on the deep origination of modern HERVs in pan-primates.


Assuntos
Retrovirus Endógenos , Animais , Cercopithecidae , Retrovirus Endógenos/genética , Evolução Molecular , Genoma Humano , Humanos , Filogenia , Platirrinos
20.
Viruses ; 14(7)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35891571

RESUMO

Human endogenous retrovirus (HERVs), normally silenced by methylation or mutations, can be reactivated by multiple environmental factors, including infections with exogenous viruses. In this work, we investigated the transcriptional activity of HERVs in human A549 cells infected by two wild-type (PR8M, SC35M) and one mutated (SC35MΔNS1) strains of Influenza A virus (IAVs). We found that the majority of differentially expressed HERVs (DEHERVS) and genes (DEGs) were up-regulated in the infected cells, with the most significantly enriched biological processes associated with the genes differentially expressed exclusively in SC35MΔNS1 being linked to the immune system. Most DEHERVs in PR8M and SC35M are mammalian apparent LTR retrotransposons, while in SC35MΔNS1, more HERV loci from the HERVW9 group were differentially expressed. Furthermore, up-regulated pairs of HERVs and genes in close chromosomal proximity to each other tended to be associated with immune responses, which implies that specific HERV groups might have the potential to trigger specific gene networks and influence host immunological pathways.


Assuntos
Retrovirus Endógenos , Vírus da Influenza A , Animais , Antivirais , Retrovirus Endógenos/genética , Humanos , Sistema Imunitário , Vírus da Influenza A/genética , Mamíferos , Retroelementos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...