Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.463
Filtrar
1.
Proc Natl Acad Sci U S A ; 121(15): e2313866121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38564639

RESUMO

Transposable element invasions have a profound impact on the evolution of genomes and phenotypes. It is thus an important open question how often such TE invasions occur. To address this question, we utilize the genomes of historical specimens, sampled about 200 y ago. We found that the LTR retrotransposons Blood, Opus, and 412 spread in Drosophila melanogaster in the 19th century. These invasions constitute second waves, as degraded fragments were found for all three TEs. The composition of Opus and 412, but not of Blood, shows a pronounced geographic heterogeneity, likely due to founder effects during the invasions. Finally, we identified species from the Drosophila simulans complex as the likely origin of the TEs. We show that in total, seven TE families invaded D. melanogaster during the last 200y, thereby increasing the genome size by up to 1.2Mbp. We suggest that this high rate of TE invasions was likely triggered by human activity. Based on the analysis of strains and specimens sampled at different times, we provide a detailed timeline of TE invasions, making D. melanogaster the first organism where the invasion history of TEs during the last two centuries could be inferred.


Assuntos
Drosophila melanogaster , Retroelementos , Animais , Humanos , Drosophila melanogaster/genética , Retroelementos/genética , Genoma , Elementos de DNA Transponíveis , Evolução Molecular
2.
Front Immunol ; 15: 1349030, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590523

RESUMO

Introduction: Parkinson's disease (PD) is a neurodegenerative and polygenic disorder characterised by the progressive loss of neural dopamine and onset of movement disorders. We previously described eight SINE-VNTR-Alu (SVA) retrotransposon-insertion-polymorphisms (RIPs) located and expressed within the Human Leucocyte Antigen (HLA) genomic region of chromosome 6 that modulate the differential co-expression of 71 different genes including the HLA classical class I and class II genes in a Parkinson's Progression Markers Initiative (PPMI) cohort. Aims and methods: In the present study, we (1) reanalysed the PPMI genomic and transcriptomic sequencing data obtained from whole blood of 1521 individuals (867 cases and 654 controls) to infer the genotypes of the transcripts expressed by eight classical HLA class I and class II genes as well as DRA and the DRB3/4/5 haplotypes, and (2) examined the statistical differences between three different PD subgroups (cases) and healthy controls (HC) for the HLA and SVA transcribed genotypes and inferred haplotypes. Results: Significant differences for 57 expressed HLA alleles (21 HLA class I and 36 HLA class II alleles) up to the three-field resolution and four of eight expressed SVA were detected at p<0.05 by the Fisher's exact test within one or other of three different PD subgroups (750 individuals with PD, 57 prodromes, 60 individuals who had scans without evidence of dopamine deficits [SWEDD]), when compared against a group of 654 HCs within the PPMI cohort and when not corrected by the Bonferroni test for multiple comparisons. Fourteen of 20 significant alleles were unique to the PD-HC comparison, whereas 31 of the 57 alleles overlapped between two or more different subgroup comparisons. Only the expressed HLA-DRA*01:01:01 and -DQA1*03:01:01 protective alleles (PD v HC), the -DQA1*03:03:01 risk (HC v Prodrome) or protective allele (PD v Prodrome), the -DRA*01:01:02 and -DRB4*01:03:02 risk alleles (SWEDD v HC), and the NR_SVA_381 present genotype (PD v HC) at a 5% homozygous insertion frequency near HLA-DPA1, were significant (Pc<0.1) after Bonferroni corrections. The homologous NR_SVA_381 insertion significantly decreased the transcription levels of HLA-DPA1 and HLA-DPB1 in the PPMI cohort and its presence as a homozygous genotype is a risk factor (Pc=0.012) for PD. The most frequent NR_SVA_381 insertion haplotype in the PPMI cohort was NR_SVA_381/DPA1*02/DPB1*01 (3.7%). Although HLA C*07/B*07/DRB5*01/DRB1*15/DQB1*06 was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the NR_SVA_381 insertion was present in only six of them (8%). Conclusions: These data suggest that expressed SVA and HLA gene alleles in circulating white blood cells are coordinated differentially in the regulation of immune responses and the long-term onset and progression of PD, the mechanisms of which have yet to be elucidated.


Assuntos
Doença de Parkinson , Retroelementos , Humanos , Retroelementos/genética , Doença de Parkinson/genética , Dopamina , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA/genética , Genótipo
3.
BMC Genomics ; 25(1): 328, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38566015

RESUMO

BACKGROUND: Whole-genome duplication and long terminal repeat retrotransposons (LTR-RTs) amplification in organisms are essential factors that affect speciation, local adaptation, and diversification of organisms. Understanding the karyotype projection and LTR-RTs amplification could contribute to untangling evolutionary history. This study compared the karyotype and LTR-RTs evolution in the genomes of eight oaks, a dominant lineage in Northern Hemisphere forests. RESULTS: Karyotype projections showed that chromosomal evolution was relatively conservative in oaks, especially on chromosomes 1 and 7. Modern oak chromosomes formed through multiple fusions, fissions, and rearrangements after an ancestral triplication event. Species-specific chromosomal rearrangements revealed fragments preserved through natural selection and adaptive evolution. A total of 441,449 full-length LTR-RTs were identified from eight oak genomes, and the number of LTR-RTs for oaks from section Cyclobalanopsis was larger than in other sections. Recent amplification of the species-specific LTR-RTs lineages resulted in significant variation in the abundance and composition of LTR-RTs among oaks. The LTR-RTs insertion suppresses gene expression, and the suppressed intensity in gene regions was larger than in promoter regions. Some centromere and rearrangement regions indicated high-density peaks of LTR/Copia and LTR/Gypsy. Different centromeric regional repeat units (32, 78, 79 bp) were detected on different Q. glauca chromosomes. CONCLUSION: Chromosome fusions and arm exchanges contribute to the formation of oak karyotypes. The composition and abundance of LTR-RTs are affected by its recent amplification. LTR-RTs random retrotransposition suppresses gene expression and is enriched in centromere and chromosomal rearrangement regions. This study provides novel insights into the evolutionary history of oak karyotypes and the organization, amplification, and function of LTR-RTs.


Assuntos
Quercus , Retroelementos , Quercus/genética , Genoma de Planta , Cariótipo , Sequências Repetidas Terminais/genética , Evolução Molecular , Filogenia
4.
Trends Cancer ; 10(4): 286-288, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38499453

RESUMO

Subsets of long interspersed nuclear element 1 (LINE-1) retrotransposons can 'retrotranspose' throughout the human genome at a cost to host cell fitness, as observed in some cancers. Pharmacological inhibition of LINE-1 retrotransposition requires a comprehensive understanding of the LINE-1 ORF2p reverse transcriptase. Two recent publications, by Thawani et al. and Baldwin et al., report structures of LINE-1 ORF2p and address long-standing mechanistic gaps regarding LINE-1 retrotransposition. Both studies will be critical to design new specific inhibitors of the LINE-1 ORF2p reverse transcriptase.


Assuntos
Elementos Nucleotídeos Longos e Dispersos , Transcrição Reversa , Humanos , Células HeLa , Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos , DNA Polimerase Dirigida por RNA/química , DNA Polimerase Dirigida por RNA/genética , DNA Polimerase Dirigida por RNA/metabolismo
5.
Mol Biol Evol ; 41(4)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38507667

RESUMO

Selfish genetic elements comprise significant fractions of mammalian genomes. In rare instances, host genomes domesticate segments of these elements for function. Using a complete human genome assembly and 25 additional vertebrate genomes, we re-analyzed the evolutionary trajectories and functional potential of capsid (CA) genes domesticated from Metaviridae, a lineage of retrovirus-like retrotransposons. Our study expands on previous analyses to unearth several new insights about the evolutionary histories of these ancient genes. We find that at least five independent domestication events occurred from diverse Metaviridae, giving rise to three universally retained single-copy genes evolving under purifying selection and two gene families unique to placental mammals, with multiple members showing evidence of rapid evolution. In the SIRH/RTL family, we find diverse amino-terminal domains, widespread loss of protein-coding capacity in RTL10 despite its retention in several mammalian lineages, and differential utilization of an ancient programmed ribosomal frameshift in RTL3 between the domesticated CA and protease domains. Our analyses also reveal that most members of the PNMA family in mammalian genomes encode a conserved putative amino-terminal RNA-binding domain (RBD) both adjoining and independent from domesticated CA domains. Our analyses lead to a significant correction of previous annotations of the essential CCDC8 gene. We show that this putative RBD is also present in several extant Metaviridae, revealing a novel protein domain configuration in retrotransposons. Collectively, our study reveals the divergent outcomes of multiple domestication events from diverse Metaviridae in the common ancestor of placental mammals.


Assuntos
Capsídeo , Retroelementos , Gravidez , Animais , Feminino , Humanos , Evolução Molecular , Placenta , Mamíferos/genética , Proteínas do Capsídeo/genética , Eutérios/genética , Filogenia
6.
Genome Res ; 34(2): 161-178, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38485193

RESUMO

Centromeres are essential regions of eukaryotic chromosomes responsible for the formation of kinetochore complexes, which connect to spindle microtubules during cell division. Notably, although centromeres maintain a conserved function in chromosome segregation, the underlying DNA sequences are diverse both within and between species and are predominantly repetitive in nature. The repeat content of centromeres includes high-copy tandem repeats (satellites), and/or specific families of transposons. The functional region of the centromere is defined by loading of a specific histone 3 variant (CENH3), which nucleates the kinetochore and shows dynamic regulation. In many plants, the centromeres are composed of satellite repeat arrays that are densely DNA methylated and invaded by centrophilic retrotransposons. In some cases, the retrotransposons become the sites of CENH3 loading. We review the structure of plant centromeres, including monocentric, holocentric, and metapolycentric architectures, which vary in the number and distribution of kinetochore attachment sites along chromosomes. We discuss how variation in CENH3 loading can drive genome elimination during early cell divisions of plant embryogenesis. We review how epigenetic state may influence centromere identity and discuss evolutionary models that seek to explain the paradoxically rapid change of centromere sequences observed across species, including the potential roles of recombination. We outline putative modes of selection that could act within the centromeres, as well as the role of repeats in driving cycles of centromere evolution. Although our primary focus is on plant genomes, we draw comparisons with animal and fungal centromeres to derive a eukaryote-wide perspective of centromere structure and function.


Assuntos
Centrômero , Retroelementos , Animais , Retroelementos/genética , Centrômero/genética , Cinetocoros , Plantas/genética , Sequências de Repetição em Tandem
7.
PLoS Genet ; 20(3): e1011200, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38470914

RESUMO

Long terminal repeat retrotransposons (LTR-RTs) are powerful mutagens regarded as a major source of genetic novelty and important drivers of evolution. Yet, the uncontrolled and potentially selfish proliferation of LTR-RTs can lead to deleterious mutations and genome instability, with large fitness costs for their host. While population genomics data suggest that an ongoing LTR-RT mobility is common in many species, the understanding of their dual role in evolution is limited. Here, we harness the genetic diversity of 320 sequenced natural accessions of the Mediterranean grass Brachypodium distachyon to characterize how genetic and environmental factors influence plant LTR-RT dynamics in the wild. When combining a coverage-based approach to estimate global LTR-RT copy number variations with mobilome-sequencing of nine accessions exposed to eight different stresses, we find little evidence for a major role of environmental factors in LTR-RT accumulations in B. distachyon natural accessions. Instead, we show that loss of RNA polymerase IV (Pol IV), which mediates RNA-directed DNA methylation in plants, results in high transcriptional and transpositional activities of RLC_BdisC024 (HOPPLA) LTR-RT family elements, and that these effects are not stress-specific. This work supports findings indicating an ongoing mobility in B. distachyon and reveals that host RNA-directed DNA methylation rather than environmental factors controls their mobility in this wild grass model.


Assuntos
Brachypodium , Retroelementos , Retroelementos/genética , Genoma de Planta/genética , Brachypodium/genética , RNA Interferente Pequeno , Variações do Número de Cópias de DNA , Sequências Repetidas Terminais/genética , Filogenia , Evolução Molecular
8.
Viruses ; 16(3)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38543768

RESUMO

LTR-retrotransposons are transposable elements characterized by the presence of long terminal repeats (LTRs) directly flanking an internal coding region. They share genome organization and replication strategies with retroviruses. Steamer-like Element-1 (MchSLE-1) is an LTR-retrotransposon identified in the genome of the Chilean blue mussel Mytilus chilensis. MchSLE-1 is transcribed; however, whether its RNA is also translated and the mechanism underlying such translation remain to be elucidated. Here, we characterize the MchSLE-1 translation mechanism. We found that the MchSLE-1 5' and 3'LTRs command transcription of sense and antisense RNAs, respectively. Using luciferase reporters commanded by the untranslated regions (UTRs) of MchSLE-1, we found that in vitro 5'UTR sense is unable to initiate translation, whereas the antisense 5'UTR initiates translation even when the eIF4E-eIF4G interaction was disrupted, suggesting the presence of an internal ribosomal entry site (IRES). The antisense 5'UTR IRES activity was tested using bicistronic reporters. The antisense 5'UTR has IRES activity only when the mRNA is transcribed in the nucleus, suggesting that nuclear RNA-binding proteins are required to modulate its activity. Indeed, heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as an IRES trans-acting factor (ITAF) of the MchSLE-1 IRES. To our knowledge, this is the first report describing an IRES in an antisense mRNA derived from a mussel LTR-retrotransposon.


Assuntos
Sítios Internos de Entrada Ribossomal , Mytilus , Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sítios Internos de Entrada Ribossomal/genética , Retroelementos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Regiões 5' não Traduzidas , Mytilus/genética , Mytilus/metabolismo , Biossíntese de Proteínas
9.
Mol Biol Evol ; 41(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38442736

RESUMO

Transposable elements drive genome evolution in all branches of life. Transposable element insertions are often deleterious to their hosts and necessitate evolution of control mechanisms to limit their spread. The long terminal repeat retrotransposon Ty1 prime (Ty1'), a subfamily of the Ty1 family, is present in many Saccharomyces cerevisiae strains, but little is known about what controls its copy number. Here, we provide evidence that a novel gene from an exapted Ty1' sequence, domesticated restriction of Ty1' relic 2 (DRT2), encodes a restriction factor that inhibits Ty1' movement. DRT2 arose through domestication of a Ty1' GAG gene and contains the C-terminal domain of capsid, which in the related Ty1 canonical subfamily functions as a self-encoded restriction factor. Bioinformatic analysis reveals the widespread nature of DRT2, its evolutionary history, and pronounced structural variation at the Ty1' relic 2 locus. Ty1' retromobility analyses demonstrate DRT2 restriction factor functionality, and northern blot and RNA-seq analysis indicate that DRT2 is transcribed in multiple strains. Velocity cosedimentation profiles indicate an association between Drt2 and Ty1' virus-like particles or assembly complexes. Chimeric Ty1' elements containing DRT2 retain retromobility, suggesting an ancestral role of productive Gag C-terminal domain of capsid functionality is present in the sequence. Unlike Ty1 canonical, Ty1' retromobility increases with copy number, suggesting that C-terminal domain of capsid-based restriction is not limited to the Ty1 canonical subfamily self-encoded restriction factor and drove the endogenization of DRT2. The discovery of an exapted Ty1' restriction factor provides insight into the evolution of the Ty1 family, evolutionary hot-spots, and host-transposable element interactions.


Assuntos
Retroelementos , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Domesticação , Elementos de DNA Transponíveis
10.
PLoS Genet ; 20(3): e1011201, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38530818

RESUMO

During the last few centuries D. melanogaster populations were invaded by several transposable elements, the most recent of which was thought to be the P-element between 1950 and 1980. Here we describe a novel TE, which we named Spoink, that has invaded D. melanogaster. It is a 5216nt LTR retrotransposon of the Ty3/gypsy superfamily. Relying on strains sampled at different times during the last century we show that Spoink invaded worldwide D. melanogaster populations after the P-element between 1983 and 1993. This invasion was likely triggered by a horizontal transfer from the D. willistoni group, much as the P-element. Spoink is probably silenced by the piRNA pathway in natural populations and about 1/3 of the examined strains have an insertion into a canonical piRNA cluster such as 42AB. Given the degree of genetic investigation of D. melanogaster it is perhaps surprising that Spoink was able to invade unnoticed.


Assuntos
Drosophila melanogaster , Retroelementos , Animais , Drosophila melanogaster/genética , RNA de Interação com Piwi , Drosophila/genética , Elementos de DNA Transponíveis
11.
Biomolecules ; 14(3)2024 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-38540776

RESUMO

Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology.


Assuntos
Esclerose Amiotrófica Lateral , Retroelementos , Humanos , Esclerose Amiotrófica Lateral/genética , Repetições Minissatélites , Elementos de DNA Transponíveis , Sistema Nervoso Central , Expressão Gênica
12.
Genome Biol ; 25(1): 63, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38439049

RESUMO

BACKGROUND: Centromeres are critical for maintaining genomic stability in eukaryotes, and their turnover shapes genome architectures and drives karyotype evolution. However, the co-evolution of centromeres from different species in allopolyploids over millions of years remains largely unknown. RESULTS: Here, we generate three near-complete genome assemblies, a tetraploid Brachypodium hybridum and its two diploid ancestors, Brachypodium distachyon and Brachypodium stacei. We detect high degrees of sequence, structural, and epigenetic variations of centromeres at base-pair resolution between closely related Brachypodium genomes, indicating the appearance and accumulation of species-specific centromere repeats from a common origin during evolution. We also find that centromere homogenization is accompanied by local satellite repeats bursting and retrotransposon purging, and the frequency of retrotransposon invasions drives the degree of interspecies centromere diversification. We further investigate the dynamics of centromeres during alloploidization process, and find that dramatic genetics and epigenetics architecture variations are associated with the turnover of centromeres between homologous chromosomal pairs from diploid to tetraploid. Additionally, our pangenomes analysis reveals the ongoing variations of satellite repeats and stable evolutionary homeostasis within centromeres among individuals of each Brachypodium genome with different polyploidy levels. CONCLUSIONS: Our results provide unprecedented information on the genomic, epigenomic, and functional diversity of highly repetitive DNA between closely related species and their allopolyploid genomes at both coarse and fine scale.


Assuntos
Brachypodium , Diploide , Humanos , Tetraploidia , Brachypodium/genética , Retroelementos , Centrômero/genética
13.
Cell Mol Life Sci ; 81(1): 92, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363375

RESUMO

The maintenance of genome integrity in the germline is crucial for mammalian development. Long interspersed element type 1 (LINE-1, L1) is a mobile genetic element that makes up about 17% of the human genome and poses a threat to genome integrity. N6-methyl-adenosine (m6A) plays an essential role in regulating various biological processes. However, the function of m6A modification in L1 retrotransposons and human germline development remains largely unknown. Here we knocked out the m6A methyltransferase METTL3 or the m6A reader YTHDF2 in human embryonic stem cells (hESCs) and discovered that METTL3 and YTHDF2 are crucial for inducing human spermatogonial stem cells (hSSCs) from hESCs in vitro. The removal of METTL3 or YTHDF2 resulted in increased L1 retrotransposition and reduced the efficiency of SSC differentiation in vitro. Further analysis showed that YTHDF2 recognizes the METTL3-catalyzed m6A modification of L1 retrotransposons and degrades L1 mRNA through autophagy, thereby blocking L1 retrotransposition. Moreover, the study confirmed that m6A modification in human fetal germ cells promotes the degradation of L1 retrotransposon RNA, preventing the insertion of new L1 retrotransposons into the genome. Interestingly, L1 retrotransposon RNA was highly expressed while METTL3 was significantly downregulated in the seminal plasma of azoospermic patients with meiotic arrest compared to males with normal fertility. Additionally, we identified some potentially pathogenic variants in m6A-related genes in azoospermic men with meiotic arrest. In summary, our study suggests that m6A modification serves as a guardian of genome stability during human germline development and provides novel insights into the function and regulatory mechanisms of m6A modification in restricting L1 retrotransposition.


Assuntos
Azoospermia , Retroelementos , Masculino , Animais , Humanos , Retroelementos/genética , RNA , Azoospermia/genética , Diferenciação Celular/genética , Metiltransferases/genética , Metiltransferases/metabolismo , RNA Mensageiro/genética , Mamíferos/metabolismo
14.
Cell Genom ; 4(2): 100504, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38359785

RESUMO

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


Assuntos
Elementos Nucleotídeos Longos e Dispersos , Retroelementos , Humanos , Retroelementos/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Genômica
15.
Sci Rep ; 14(1): 4322, 2024 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383551

RESUMO

Long interspersed nuclear elements (LINE-1s/L1s) are a group of retrotransposons that can copy themselves within a genome. In humans, it is the most successful transposon in nucleotide content. L1 expression is generally mild in normal human tissues, but the activity has been shown to increase significantly in many cancers. Few studies have examined L1 expression at single-cell resolution, thus it is undetermined whether L1 reactivation occurs solely in malignant cells within tumors. One of the cancer types with frequent L1 activity is high-grade serous ovarian carcinoma (HGSOC). Here, we identified locus-specific L1 expression with 3' single-cell RNA sequencing in pre- and post-chemotherapy HGSOC sample pairs from 11 patients, and in fallopian tube samples from five healthy women. Although L1 expression quantification with the chosen technique was challenging due to the repetitive nature of the element, we found evidence of L1 expression primarily in cancer cells, but also in other cell types, e.g. cancer-associated fibroblasts. The expression levels were similar in samples taken before and after neoadjuvant chemotherapy, indicating that L1 transcriptional activity was unaffected by clinical platinum-taxane treatment. Furthermore, L1 activity was negatively associated with the expression of MYC target genes, a finding that supports earlier literature of MYC being an L1 suppressor.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos/genética , Tubas Uterinas/metabolismo
16.
Int J Mol Sci ; 25(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38339043

RESUMO

Programmed ribosomal frameshifting (PRF) exists in all branches of life that regulate gene expression at the translational level. The eukaryotic translation initiation factor 5A (eIF5A) is a highly conserved protein essential in all eukaryotes. It is identified initially as an initiation factor and functions broadly in translation elongation and termination. The hypusination of eIF5A is specifically required for +1 PRF at the shifty site derived from the ornithine decarboxylase antizyme 1 (OAZ1) in Saccharomyces cerevisiae. However, whether the regulation of +1 PRF by yeast eIF5A is universal remains unknown. Here, we found that Sc-eIF5A depletion decreased the putrescine/spermidine ratio. The re-introduction of Sc-eIF5A in yeast eIF5A mutants recovered the putrescine/spermidine ratio. In addition, the Sc-eIF5A depletion decreases +1 PRF during the decoding of Ty1 retrotransposon mRNA, but has no effect on -1 PRF during the decoding of L-A virus mRNA. The re-introduction of Sc-eIF5A in yeast eIF5A mutants restored the +1 PRF rate of Ty1. The inhibition of the hypusine modification of yeast eIF5A by GC7 treatment or by mutating the hypusination site Lys to Arg caused decreases of +1 PRF rates in the Ty1 retrotransposon. Furthermore, mutational studies of the Ty1 frameshifting element support a model where the efficient removal of ribosomal subunits at the first Ty1 frame 0 stop codon is required for the frameshifting of trailing ribosomes. This dependency is likely due to the unique position of the frame 0 stop codon distance from the slippery sequence of Ty1. The results showed that eIF5A is a trans-regulator of +1 PRF for Ty1 retrotransposon and could function universally in yeast.


Assuntos
Mudança da Fase de Leitura do Gene Ribossômico , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Espermidina/metabolismo , Putrescina/metabolismo , Retroelementos/genética , Códon de Terminação/genética , Códon de Terminação/metabolismo , Fatores de Iniciação de Peptídeos/genética , Fatores de Iniciação de Peptídeos/metabolismo
17.
Cell Genom ; 4(2): 100498, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38309261

RESUMO

Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- and long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, and individual loci and elucidate key principles involved. We find that the youngest primate L1 families are specifically hypomethylated in pluripotent stem cells and the placenta but not in most tumors. Locally, intronic L1 methylation is intimately associated with gene transcription. Conversely, the L1 methylation state can propagate to the proximal region up to 300 bp. This phenomenon is accompanied by the binding of specific transcription factors, which drive the expression of L1 and chimeric transcripts. Finally, L1 hypomethylation alone is typically insufficient to trigger L1 expression due to redundant silencing pathways. Our results illuminate the epigenetic and transcriptional interplay between retrotransposons and their host genome.


Assuntos
Metilação de DNA , Retroelementos , Animais , Humanos , Retroelementos/genética , Metilação de DNA/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Fatores de Transcrição/genética , Primatas/genética , Epigênese Genética/genética
18.
Cell Rep ; 43(2): 113749, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38329876

RESUMO

Aberrant long interspersed element 1 (LINE-1 or L1) activity can cause insertional mutagenesis and chromosomal rearrangements and has been detected in several types of cancers. Here, we show that neddylation, a post-translational modification process, is essential for L1 transposition. The antineoplastic drug MLN4924 is an L1 inhibitor that suppresses NEDD8-activating enzyme activity. Neddylation inhibition by MLN4924 selectively impairs ORF2p-mediated L1 reverse transcription and blocks the generation of L1 cDNA. Consistent with these results, MLN4924 treatment suppresses the retrotransposition activity of the non-autonomous retrotransposons short interspersed nuclear element R/variable number of tandem repeat/Alu and Alu, which rely on the reverse transcription activity of L1 ORF2p. The E2 enzyme UBE2M in the neddylation pathway, rather than UBE2F, is required for L1 ORF2p and retrotransposition. Interference with the functions of certain neddylation-dependent Cullin-really interesting new gene E3 ligases disrupts L1 reverse transcription and transposition activity. Our findings provide insights into the regulation of L1 retrotransposition and the identification of therapeutic targets for L1 dysfunctions.


Assuntos
Ciclopentanos , Elementos Nucleotídeos Longos e Dispersos , Pirimidinas , Retroelementos , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos/genética , Aberrações Cromossômicas , Proteínas Culina/genética , Enzimas de Conjugação de Ubiquitina
19.
Proc Natl Acad Sci U S A ; 121(9): e2316469121, 2024 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-38354254

RESUMO

Diversity-generating retroelements (DGRs) are used by bacteria, archaea, and viruses as a targeted mutagenesis tool. Through error-prone reverse transcription, DGRs introduce random mutations at specific genomic loci, enabling rapid evolution of these targeted genes. However, the function and benefits of DGR-diversified proteins in cellular hosts remain elusive. We find that 82% of DGRs from one of the major monophyletic lineages of DGR reverse transcriptases are encoded by multicellular bacteria, which often have two or more DGR loci in their genomes. Using the multicellular purple sulfur bacterium Thiohalocapsa sp. PB-PSB1 as an example, we characterized nine distinct DGR loci capable of generating 10282 different combinations of target proteins. With environmental metagenomes from individual Thiohalocapsa aggregates, we show that most of PB-PSB1's DGR target genes are diversified across its biogeographic range, with spatial heterogeneity in the diversity of each locus. In Thiohalocapsa PB-PSB1 and other bacteria hosting this lineage of cellular DGRs, the diversified target genes are associated with NACHT-domain anti-phage defenses and putative ternary conflict systems previously shown to be enriched in multicellular bacteria. We propose that these DGR-diversified targets act as antigen sensors that confer a form of adaptive immunity to their multicellular consortia, though this remains to be experimentally tested. These findings could have implications for understanding the evolution of multicellularity, as the NACHT-domain anti-phage systems and ternary systems share both domain homology and conceptual similarities with the innate immune and programmed cell death pathways of plants and metazoans.


Assuntos
Bactérias , Bacteriófagos , Bactérias/genética , Archaea/genética , Metagenoma , Retroelementos , Bacteriófagos/genética
20.
Cancer Res Commun ; 4(2): 540-555, 2024 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-38358346

RESUMO

Type I IFN signaling is a crucial component of antiviral immunity that has been linked to promoting the efficacy of some chemotherapeutic drugs. We developed a reporter system in HCT116 cells that detects activation of the endogenous IFI27 locus, an IFN target gene. We screened a library of annotated compounds in these cells and discovered Aurora kinase inhibitors (AURKi) as strong hits. Type I IFN signaling was found to be the most enriched gene signature after AURKi treatment in HCT116, and this signature was also strongly enriched in other colorectal cancer cell lines. The ability of AURKi to activate IFN in HCT116 was dependent on MAVS and RIG-I, but independent of STING, whose signaling is deficient in these cells. MAVS dependence was recapitulated in other colorectal cancer lines with STING pathway deficiency, whereas in cells with intact STING signaling, the STING pathway was required for IFN induction by AURKi. AURKis were found to induce expression of endogenous retroviruses (ERV). These ERVs were distinct from those induced by the DNA methyltransferase inhibitors (DNMTi), which can induce IFN signaling via ERV induction, suggesting a novel mechanism of action. The antitumor effect of alisertib in mice was accompanied by an induction of IFN expression in HCT116 or CT26 tumors. CT26 tumor growth inhibition by alisertib was absent in NSG mice versus wildtype (WT) mice, and tumors from WT mice with alisertib treatment showed increased in CD8+ T-cell infiltration, suggesting that antitumor efficacy of AURKi depends, at least in part, on an intact immune response. SIGNIFICANCE: Some cancers deactivate STING signaling to avoid consequences of DNA damage from aberrant cell division. The surprising activation of MAVS/RIG-I signaling by AURKi might represent a vulnerability in STING signaling deficient cancers.


Assuntos
Neoplasias Colorretais , Interferon Tipo I , Animais , Camundongos , Retroelementos , Interferon lambda , Aurora Quinases/metabolismo , Interferon Tipo I/metabolismo , Proteína DEAD-box 58/genética , Receptores Imunológicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...