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Nature Genetics Dec 2023Identifying genes linked to extreme phenotypes in humans has the potential to highlight biological processes not shared with all other mammals. Here, we report the...
Identifying genes linked to extreme phenotypes in humans has the potential to highlight biological processes not shared with all other mammals. Here, we report the identification of homozygous loss-of-function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein family, a large and rapidly evolving group of epigenetic silencers which target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of regulatory potential contained in the primate-specific transposable elements it represses during early pancreas development. This leads to inappropriate specification of cell fate with induction of genes associated with liver identity. Our results highlight the essential role of ZNF808 in pancreatic development in humans and the contribution of primate-specific regions of the human genome to congenital developmental disease.
Topics: Animals; Humans; Cell Differentiation; DNA Transposable Elements; Genome, Human; Primates; DNA-Binding Proteins; Congenital Abnormalities; Pancreas
PubMed: 37973953
DOI: 10.1038/s41588-023-01565-x -
Cell Reports Jul 2023Prokaryotic adaptation is strongly influenced by the horizontal acquisition of beneficial traits via mobile genetic elements (MGEs), such as viruses/bacteriophages and... (Review)
Review
Prokaryotic adaptation is strongly influenced by the horizontal acquisition of beneficial traits via mobile genetic elements (MGEs), such as viruses/bacteriophages and plasmids. However, MGEs can also impose a fitness cost due to their often parasitic nature and differing evolutionary trajectories. In response, prokaryotes have evolved diverse immune mechanisms against MGEs. Recently, our understanding of the abundance and diversity of prokaryotic immune systems has greatly expanded. These defense systems can degrade the invading genetic material, inhibit genome replication, or trigger abortive infection, leading to population protection. In this review, we highlight these strategies, focusing on the most recent discoveries. The study of prokaryotic defenses not only sheds light on microbial evolution but also uncovers novel enzymatic activities with promising biotechnological applications.
Topics: Prokaryotic Cells; Plasmids; Bacteriophages; Genome; Interspersed Repetitive Sequences
PubMed: 37347666
DOI: 10.1016/j.celrep.2023.112672 -
Proceedings of the National Academy of... Oct 2023Chronic lymphocytic leukemia (CLL) is one of the most diagnosed forms of leukemia worldwide and it is usually classified into two forms: indolent and aggressive. These...
Chronic lymphocytic leukemia (CLL) is one of the most diagnosed forms of leukemia worldwide and it is usually classified into two forms: indolent and aggressive. These two forms are characterized by distinct molecular features that drive different responses to treatment and clinical outcomes. In this context, a better understanding of the molecular landscape of the CLL forms may potentially lead to the development of new drugs or the identification of novel biomarkers. Human endogenous retroviruses (HERVs) are a class of transposable elements that have been associated with the development of different human cancers, including different forms of leukemias. However, no studies about HERVs in CLL have ever been reported so far. Here, we present the first locus-specific profiling of HERV expression in both the aggressive and indolent forms of CLL. Our analyses revealed several dysregulations in HERV expression occurring in CLL and some of them were specific for either the aggressive or indolent form of CLL. Such results were also validated by analyzing an external cohort of CLL patients and by RT-qPCR. Moreover, in silico analyses have shown relevant signaling pathways associated with them suggesting a potential involvement of the dysregulated HERVs in these pathways and consequently in CLL development.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Endogenous Retroviruses; Biomarkers
PubMed: 37871223
DOI: 10.1073/pnas.2307593120 -
Genes & Genetic Systems Feb 2024Retrotransposons, which account for approximately 42% of the human genome, have been increasingly recognized as "non-self" pathogen-associated molecular patterns (PAMPs)... (Review)
Review
Retrotransposons, which account for approximately 42% of the human genome, have been increasingly recognized as "non-self" pathogen-associated molecular patterns (PAMPs) due to their virus-like sequences. In abnormal conditions such as cancer and viral infections, retrotransposons that are aberrantly expressed due to impaired epigenetic suppression display PAMPs, leading to their recognition by pattern recognition receptors (PRRs) of the innate immune system and triggering inflammation. This viral mimicry mechanism has been observed in various human diseases, including aging and autoimmune disorders. However, recent evidence suggests that retrotransposons possess highly regulated immune reactivity and play important roles in the development and function of the immune system. In this review, I discuss a wide range of retrotransposon-derived transcripts, their role as targets in immune recognition, and the diseases associated with retrotransposon activity. Furthermore, I explore the implications of chimeric transcripts formed between retrotransposons and known gene mRNAs, which have been previously underestimated, for the increase of immune-related gene isoforms and their influence on immune function. Retrotransposon-derived transcripts have profound and multifaceted effects on immune system function. The aim of this comprehensive review is to provide a better understanding of the complex relationship between retrotransposon transcripts and immune defense.
Topics: Humans; Retroelements; Pathogen-Associated Molecular Pattern Molecules; RNA, Messenger; Genome, Human; Immunity, Innate
PubMed: 38199240
DOI: 10.1266/ggs.23-00187 -
Nature Communications Aug 2023Endogenous retroviruses (ERVs) record past retroviral infections, providing molecular archives for interrogating the evolution of retroviruses and retrovirus-host...
Endogenous retroviruses (ERVs) record past retroviral infections, providing molecular archives for interrogating the evolution of retroviruses and retrovirus-host interaction. However, the vast majority of ERVs are not active anymore due to various disruptive mutations, and ongoing retroviral invasion of vertebrate genomes has been rarely documented. Here we analyze genomics data from 2004 vertebrates for mining invading ERVs (ERVi). We find that at least 412 ERVi elements representing 217 viral operational taxonomic units are invading the genomes of 123 vertebrates, 18 of which have been assessed to be threatened species. Our results reveal an unexpected prevalence of ongoing retroviral invasion in vertebrates and expand the diversity of retroviruses recently circulating in the wild. We characterize the pattern and nature of ERVi in the historical and biogeographical context of their hosts, for instance, the generation of model organisms, sympatric speciation, and domestication. We suspect that these ERVi are relevant to conservation of threatened species, zoonoses in the wild, and emerging infectious diseases in humans.
Topics: Humans; Animals; Endogenous Retroviruses; Genomics; Communicable Diseases, Emerging; Domestication; Endangered Species; Vertebrates
PubMed: 37591904
DOI: 10.1038/s41467-023-40732-w -
Nature Communications Nov 2023Transposable elements (TEs) comprise ~85% of the common wheat genome, which are highly diverse among subgenomes, possibly contribute to polyploid plasticity, but the...
Transposable elements (TEs) comprise ~85% of the common wheat genome, which are highly diverse among subgenomes, possibly contribute to polyploid plasticity, but the causality is only assumed. Here, by integrating data from gene expression cap analysis and epigenome profiling via hidden Markov model in common wheat, we detect a large proportion of enhancer-like elements (ELEs) derived from TEs producing nascent noncoding transcripts, namely ELE-RNAs, which are well indicative of the regulatory activity of ELEs. Quantifying ELE-RNA transcriptome across typical developmental stages reveals that TE-initiated ELE-RNAs are mainly from RLG_famc7.3 specifically expanded in subgenome A. Acquisition of spike-specific transcription factor binding likely confers spike-specific expression of RLG_famc7.3-initiated ELE-RNAs. Knockdown of RLG_famc7.3-initiated ELE-RNAs resulted in global downregulation of spike-specific genes and abnormal spike development. These findings link TE expansion to regulatory specificity and polyploid developmental plasticity, highlighting the functional impact of TE-driven regulatory innovation on polyploid evolution.
Topics: DNA Transposable Elements; Triticum; Gene Expression Regulation; Polyploidy; Transcriptome; RNA
PubMed: 37978184
DOI: 10.1038/s41467-023-42771-9 -
Journal of Translational Medicine Dec 2023Glioblastoma (GBM) comprises 45.6% of all primary malignant brain cancers and is one of the most common and aggressive intracranial tumors in adults. Intratumoral... (Review)
Review
Glioblastoma (GBM) comprises 45.6% of all primary malignant brain cancers and is one of the most common and aggressive intracranial tumors in adults. Intratumoral heterogeneity with a wide range of proteomic, genetic, and epigenetic dysregulation contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. To date, numerous clinical trials have been developed to target the proteome and epigenome of high-grade gliomas with promising results. However, studying RNA modifications, or RNA epitranscriptomics, is a new frontier within neuro-oncology. RNA epitranscriptomics was discovered in the 1970s, but in the last decade, the extent of modification of mRNA and various non-coding RNAs has emerged and been implicated in transposable element activation and many other oncogenic processes within the tumor microenvironment. This review provides background information and discusses the therapeutic potential of agents modulating epitranscriptomics in high-grade gliomas. A particular emphasis will be placed on how combination therapies that include immune agents targeting hERV-mediated viral mimicry could improve the treatment of GBM.
Topics: Adult; Humans; Endogenous Retroviruses; Tumor Microenvironment; Proteomics; Glioma; Glioblastoma; Brain Neoplasms; RNA, Messenger
PubMed: 38071304
DOI: 10.1186/s12967-023-04725-z -
Microbial Biotechnology Jan 2024Mobile genetic elements (MGEs) are crucial for horizontal gene transfer (HGT) in bacteria and facilitate their rapid evolution and adaptation. MGEs include plasmids,... (Review)
Review
Mobile genetic elements (MGEs) are crucial for horizontal gene transfer (HGT) in bacteria and facilitate their rapid evolution and adaptation. MGEs include plasmids, integrative and conjugative elements, transposons, insertion sequences and bacteriophages. Notably, the spread of antimicrobial resistance genes (ARGs), which poses a serious threat to public health, is primarily attributable to HGT through MGEs. This mini-review aims to provide an overview of the mechanisms by which MGEs mediate HGT in microbes. Specifically, the behaviour of conjugative plasmids in different environments and conditions was discussed, and recent methodologies for tracing the dynamics of MGEs were summarised. A comprehensive understanding of the mechanisms underlying HGT and the role of MGEs in bacterial evolution and adaptation is important to develop strategies to combat the spread of ARGs.
Topics: Interspersed Repetitive Sequences; Gene Transfer, Horizontal; Plasmids; Bacteria; Bacteriophages; Anti-Bacterial Agents
PubMed: 38226780
DOI: 10.1111/1751-7915.14408 -
FEBS Open Bio Jan 2024Transposons are mobile genetic elements that have invaded all domains of life by moving between and within their host genomes. Due to their mobility (or transposition),... (Review)
Review
Transposons are mobile genetic elements that have invaded all domains of life by moving between and within their host genomes. Due to their mobility (or transposition), transposons facilitate horizontal gene transfer in bacteria and foster the evolution of new molecular functions in prokaryotes and eukaryotes. As transposition can lead to detrimental genomic rearrangements, organisms have evolved a multitude of molecular strategies to control transposons, including genome defense mechanisms provided by CRISPR-Cas systems. Apart from their biological impacts on genomes, DNA transposons have been leveraged as efficient gene insertion vectors in basic research, transgenesis and gene therapy. However, the close to random insertion profile of transposon-based tools limits their programmability and safety. Despite recent advances brought by the development of CRISPR-associated genome editing nucleases, a strategy for efficient insertion of large, multi-kilobase transgenes at user-defined genomic sites is currently challenging. The discovery and experimental characterization of bacterial CRISPR-associated transposons (CASTs) led to the attractive hypothesis that these systems could be repurposed as programmable, site-specific gene integration technologies. Here, we provide a broad overview of the molecular mechanisms underpinning DNA transposition and of its biological and technological impact. The second focus of the article is to describe recent mechanistic and functional analyses of CAST transposition. Finally, current challenges and desired future advances of CAST-based genome engineering applications are briefly discussed.
Topics: DNA Transposable Elements; Mutagenesis, Insertional; Bacteria; CRISPR-Cas Systems; Gene Transfer Techniques
PubMed: 38041553
DOI: 10.1002/2211-5463.13743 -
Cell Reports Nov 2023Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes...
Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.
Topics: Humans; Animals; Mice; Endogenous Retroviruses; Neuroinflammatory Diseases; Transcriptome; Brain Injuries, Traumatic; Brain Injuries; Oligodendroglia; Inflammation; Mice, Inbred C57BL
PubMed: 37967557
DOI: 10.1016/j.celrep.2023.113395