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Current Opinion in Plant Biology Oct 2023The relationship of transposable elements (TEs) with their host genomes has usually been seen as an arms race between TEs and their host genomes. Consequently, TEs are... (Review)
Review
The relationship of transposable elements (TEs) with their host genomes has usually been seen as an arms race between TEs and their host genomes. Consequently, TEs are supposed to amplify by bursts of transposition, when the TE escapes host surveillance, followed by long periods of TE quiescence and efficient host control. Recent data obtained from an increasing number of assembled plant genomes and resequencing population datasets show that TE dynamics is more complex and varies among TE families and their host genomes. This variation ranges from large genomes that accommodate large TE populations to genomes that are very active in TE elimination, and from inconspicuous elements with very low activity to elements with high transposition and elimination rates. The dynamics of each TE family results from a long history of interaction with the host in a genome populated by many other TE families, very much like an evolving ecosystem.
Topics: DNA Transposable Elements; Ecosystem; Genome, Plant; Evolution, Molecular
PubMed: 37459733
DOI: 10.1016/j.pbi.2023.102418 -
The Journal of Clinical Investigation Jul 2023Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterize most cancer types and are linked with disease outcomes. However, the...
Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterize most cancer types and are linked with disease outcomes. However, the underlying processes are incompletely understood. Here, we show that elevated transcription of HERVH proviruses predicted survival of lung squamous cell carcinoma (LUSC) and identified an isoform of CALB1, encoding calbindin, ectopically driven by an upstream HERVH provirus under the control of KLF5, as the mediator of this effect. HERVH-CALB1 expression was initiated in preinvasive lesions and associated with their progression. Calbindin loss in LUSC cell lines impaired in vitro and in vivo growth and triggered senescence, consistent with a protumor effect. However, calbindin also directly controlled the senescence-associated secretory phenotype (SASP), marked by secretion of CXCL8 and other neutrophil chemoattractants. In established carcinomas, CALB1-negative cancer cells became the dominant source of CXCL8, correlating with neutrophil infiltration and worse prognosis. Thus, HERVH-CALB1 expression in LUSC may display antagonistic pleiotropy, whereby the benefits of escaping senescence early during cancer initiation and clonal competition were offset by the prevention of SASP and protumor inflammation at later stages.
Topics: Humans; Calbindins; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cellular Senescence; Endogenous Retroviruses; Lung Neoplasms; Proviruses
PubMed: 37192000
DOI: 10.1172/JCI164397 -
Science Advances Nov 2023The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element-1 (L1)...
The genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element-1 (L1) retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type-specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, , is a human-specific transcript expressed exclusively during brain development. CRISPR interference silencing of results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.
Topics: Animals; Humans; Retroelements; Transcriptome; Long Interspersed Nucleotide Elements; Neurons; Primates
PubMed: 37910626
DOI: 10.1126/sciadv.adh9543 -
Journal of Molecular Medicine (Berlin,... Dec 2023In this review, we summarized the results of experimental and clinical studies about three human endogenous retroviruses and their products-syncytin-1, syncytin-2, and... (Review)
Review
In this review, we summarized the results of experimental and clinical studies about three human endogenous retroviruses and their products-syncytin-1, syncytin-2, and suppressyn in human physiology and pathophysiology. We summed up the described connection with various pathological processes and diseases, mainly with pregnancy-induced hypertensive diseases such as preeclampsia, oncogenesis, gestational trophoblastic disease, and multiple sclerosis. Supposed mechanisms of action and the potential of clinical applications are also described.
Topics: Pregnancy; Female; Humans; Placenta; Gene Products, env; Pregnancy Proteins; Endogenous Retroviruses; Pre-Eclampsia
PubMed: 37855856
DOI: 10.1007/s00109-023-02385-6 -
Cell Reports Jun 2023Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell...
Endogenous retroviruses (ERVs) have rewired host gene networks. To explore the origins of co-option, we employed an active murine ERV, IAPEz, and an embryonic stem cell (ESC) to neural progenitor cell (NPC) differentiation model. Transcriptional silencing via TRIM28 maps to a 190 bp sequence encoding the intracisternal A-type particle (IAP) signal peptide, which confers retrotransposition activity. A subset of "escapee" IAPs (∼15%) exhibits significant genetic divergence from this sequence. Canonical repressed IAPs succumb to a previously undocumented demarcation by H3K9me3 and H3K27me3 in NPCs. Escapee IAPs, in contrast, evade repression in both cell types, resulting in their transcriptional derepression, particularly in NPCs. We validate the enhancer function of a 47 bp sequence within the U3 region of the long terminal repeat (LTR) and show that escapee IAPs convey an activating effect on nearby neural genes. In sum, co-opted ERVs stem from genetic escapees that have lost vital sequences required for both TRIM28 restriction and autonomous retrotransposition.
Topics: Animals; Mice; Cell Differentiation; Embryonic Stem Cells; Endogenous Retroviruses; Histones; Tripartite Motif-Containing Protein 28; Terminal Repeat Sequences
PubMed: 37294634
DOI: 10.1016/j.celrep.2023.112625 -
Biomolecules Oct 2023Endogenous retroviruses (ERVs) are retrovirus-like sequences that were previously integrated into the host genome. Although most ERVs are inactivated by mutations,... (Review)
Review
Endogenous retroviruses (ERVs) are retrovirus-like sequences that were previously integrated into the host genome. Although most ERVs are inactivated by mutations, deletions, or epigenetic regulation, some remain transcriptionally active and impact host physiology. Several ERV-encoded proteins, such as Syncytins and Suppressyn, contribute to placenta acquisition, a crucial adaptation in mammals that protects the fetus from external threats and other risks while enabling the maternal supply of oxygen, nutrients, and antibodies. In primates, Syncytin-1 and Syncytin-2 facilitate cell-cell fusion for placental formation. Suppressyn is the first ERV-derived protein that inhibits cell fusion by binding to ASCT2, the receptor for Syncytin-1. Furthermore, Syncytin-2 likely inserted into the genome of the common ancestor of Anthropoidea, whereas Syncytin-1 and Suppressyn likely inserted into the ancestor of catarrhines; however, they were inactivated in some lineages, suggesting that multiple exaptation events had occurred. This review discusses the role of ERV-encoded proteins, particularly Syncytins and Suppressyn, in placental development and function, focusing on the integration of ERVs into the host genome and their contribution to the genetic mechanisms underlying placentogenesis. This review provides valuable insights into the molecular and genetic aspects of placentation, potentially shedding light on broader evolutionary and physiological processes in mammals.
Topics: Animals; Pregnancy; Female; Placenta; Endogenous Retroviruses; Epigenesis, Genetic; Placentation; Gene Products, env; Mammals
PubMed: 37892164
DOI: 10.3390/biom13101482 -
Genome Research Aug 2023Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups of transcription factors encoded by tetrapods, with 378...
Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups of transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes are often grouped in clusters reflecting amplification by gene and segment duplication since the gene family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, and that KZFPs facilitate the co-option of the regulatory potential of TEs for the benefit of the host. Here, we present a comprehensive survey of the genetic features and genomic targets of human KZFPs, notably completing past analyses by adding data on close to a hundred family members. General principles emerge from our study of the TE-KZFP regulatory system, which point to multipronged evolutionary mechanisms underlaid by highly complex and combinatorial modes of action with strong influences on human speciation.
Topics: Humans; DNA Transposable Elements; Genomics; Transcription Factors; Zinc Fingers; Evolution, Molecular; Gene Expression Regulation
PubMed: 37730438
DOI: 10.1101/gr.277722.123 -
Trends in Genetics : TIG Feb 2024Endogenous retroviruses (ERVs) are inherited genomic remains of past germline retroviral infections. Research on human ERVs has focused on medical implications of their... (Review)
Review
Endogenous retroviruses (ERVs) are inherited genomic remains of past germline retroviral infections. Research on human ERVs has focused on medical implications of their dysregulation on various diseases. However, recent studies incorporating wildlife are yielding remarkable perspectives on long-term retrovirus-host interactions. These initial forays into broader taxonomic analysis, including sequencing of multiple individuals per species, show the incredible plasticity and variation of ERVs within and among wildlife species. This demonstrates that stochastic processes govern much of the vertebrate genome. In this review, we elaborate on discoveries pertaining to wildlife ERV origins and evolution, genome colonization, and consequences for host biology.
Topics: Animals; Humans; Endogenous Retroviruses; Animals, Wild; Vertebrates; Genomics; Evolution, Molecular; Phylogeny
PubMed: 37985317
DOI: 10.1016/j.tig.2023.10.014 -
Genes Oct 2023Three mobile element classes, namely , LINE-1 (L1), and SVA elements, remain actively mobile in human genomes and continue to produce new mobile element insertions... (Review)
Review
Three mobile element classes, namely , LINE-1 (L1), and SVA elements, remain actively mobile in human genomes and continue to produce new mobile element insertions (MEIs). Historically, MEIs have been discovered and studied using several methods, including: (1) Southern blots, (2) PCR (including PCR display), and (3) the detection of MEI copies from young subfamilies. We are now entering a new phase of MEI discovery where these methods are being replaced by whole genome sequencing and bioinformatics analysis to discover novel MEIs. We expect that the universe of sequenced human genomes will continue to expand rapidly over the next several years, both with short-read and long-read technologies. These resources will provide unprecedented opportunities to discover MEIs and study their impact on human traits and diseases. They also will allow the MEI community to discover and study the source elements that produce these new MEIs, which will facilitate our ability to study source element regulation in various tissue contexts and disease states. This, in turn, will allow us to better understand MEI mutagenesis in humans and the impact of this mutagenesis on human biology.
Topics: Animals; Humans; Genome, Human; Hominidae; Computational Biology; Whole Genome Sequencing; Long Interspersed Nucleotide Elements
PubMed: 37895272
DOI: 10.3390/genes14101923 -
Viruses Oct 2023Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite...
Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.
Topics: Humans; HIV-1; Virus Latency; Proviruses; Endogenous Retroviruses; HIV Infections; HIV Seropositivity; CD4-Positive T-Lymphocytes
PubMed: 38005849
DOI: 10.3390/v15112171