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Cell Aug 2022Bacteria encode sophisticated anti-phage systems that are diverse and versatile and display high genetic mobility. How this variability and mobility occurs remains...
Bacteria encode sophisticated anti-phage systems that are diverse and versatile and display high genetic mobility. How this variability and mobility occurs remains largely unknown. Here, we demonstrate that a widespread family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs), carry an impressive arsenal of defense mechanisms, which can be disseminated intra- and inter-generically by helper phages. These defense systems provide broad immunity, blocking not only phage reproduction, but also plasmid and non-cognate PICI transfer. Our results demonstrate that phages can mobilize PICI-encoded immunity systems to use them against other mobile genetic elements, which compete with the phages for the same bacterial hosts. Therefore, despite the cost, mobilization of PICIs may be beneficial for phages, PICIs, and bacteria in nature. Our results suggest that PICIs are important players controlling horizontal gene transfer and that PICIs and phages establish mutualistic interactions that drive bacterial ecology and evolution.
Topics: Bacteria; Bacteriophages; Gene Transfer, Horizontal; Genomic Islands; Immune System; Plasmids
PubMed: 35985290
DOI: 10.1016/j.cell.2022.07.014 -
International Journal of Molecular... Nov 2022In the last fifty years, large efforts have been deployed in basic research, clinical oncology, and clinical trials, yielding an enormous amount of information regarding... (Review)
Review
In the last fifty years, large efforts have been deployed in basic research, clinical oncology, and clinical trials, yielding an enormous amount of information regarding the molecular mechanisms of cancer and the design of effective therapies. The knowledge that has accumulated underpins the complexity, multifactoriality, and heterogeneity of cancer, disclosing novel landscapes in cancer biology with a key role of genome plasticity. Here, we propose that cancer onset and progression are determined by a stress-responsive epigenetic mechanism, resulting from the convergence of upregulation of (), the largest family of human retrotransposons, genome damage, nuclear lamina fragmentation, chromatin remodeling, genome reprogramming, and autophagy activation. The upregulated expression of retrotransposons and their protein products plays a key role in these processes, yielding an increased plasticity of the nuclear architecture with the ensuing reprogramming of global gene expression, including the reactivation of embryonic transcription profiles. Cancer phenotypes would thus emerge as a consequence of the unscheduled reactivation of embryonic gene expression patterns in an inappropriate context, triggering de-differentiation and aberrant proliferation in differentiated cells. Depending on the intensity of the stressing stimuli and the level of response, diverse degrees of malignity would be generated.
Topics: Humans; Long Interspersed Nucleotide Elements; Neoplasms; Cell Differentiation; Retroelements; Epigenesis, Genetic
PubMed: 36498938
DOI: 10.3390/ijms232314610 -
Cold Spring Harbor Perspectives in... May 2022One of the most fundamental questions in developmental biology is how one fertilized cell can give rise to a fully mature organism and how gene regulation governs this... (Review)
Review
One of the most fundamental questions in developmental biology is how one fertilized cell can give rise to a fully mature organism and how gene regulation governs this process. Precise spatiotemporal gene expression is required for development and is believed to be achieved through a complex interplay of sequence-specific information, epigenetic modifications, -acting factors, and chromatin folding. Here we review the role of chromatin folding during development, the mechanisms governing 3D genome organization, and how it is established in the embryo. Furthermore, we discuss recent advances and debated questions regarding the contribution of the 3D genome to gene regulation during organogenesis. Finally, we describe the mechanisms that can reshape the 3D genome, including disease-causing structural variations and the emerging view that transposable elements contribute to chromatin organization.
Topics: Chromatin; DNA Transposable Elements; Embryo, Mammalian; Epigenesis, Genetic; Gene Expression Regulation
PubMed: 34312246
DOI: 10.1101/cshperspect.a040188 -
Cell Research Jun 2021Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation. In an effort...
Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation. In an effort to unravel the basic principle underlying genome folding, here we focus on the genome itself and report a fundamental role for L1 (LINE1 or LINE-1) and B1/Alu retrotransposons, the most abundant subclasses of repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering of L1 and B1/Alu demarcates the genome into grossly exclusive domains, and characterizes and predicts Hi-C compartments. Spatial segregation of L1-rich sequences in the nuclear and nucleolar peripheries and B1/Alu-rich sequences in the nuclear interior is conserved in mouse and human cells and occurs dynamically during the cell cycle. In addition, de novo establishment of L1 and B1 nuclear segregation is coincident with the formation of higher-order chromatin structures during early embryogenesis and appears to be critically regulated by L1 and B1 transcripts. Importantly, depletion of L1 transcripts in embryonic stem cells drastically weakens homotypic repeat contacts and compartmental strength, and disrupts the nuclear segregation of L1- or B1-rich chromosomal sequences at genome-wide and individual sites. Mechanistically, nuclear co-localization and liquid droplet formation of L1 repeat DNA and RNA with heterochromatin protein HP1α suggest a phase-separation mechanism by which L1 promotes heterochromatin compartmentalization. Taken together, we propose a genetically encoded model in which L1 and B1/Alu repeats blueprint chromatin macrostructure. Our model explains the robustness of genome folding into a common conserved core, on which dynamic gene regulation is overlaid across cells.
Topics: Animals; Cluster Analysis; Long Interspersed Nucleotide Elements; Mice; RNA; Repetitive Sequences, Nucleic Acid; Retroelements
PubMed: 33514913
DOI: 10.1038/s41422-020-00466-6 -
PLoS Genetics Apr 2020As the maternal-foetal interface, the placenta is essential for the establishment and progression of healthy pregnancy, regulating both foetal growth and maternal... (Review)
Review
As the maternal-foetal interface, the placenta is essential for the establishment and progression of healthy pregnancy, regulating both foetal growth and maternal adaptation to pregnancy. The evolution and functional importance of genomic imprinting are inextricably linked to mammalian placentation. Recent technological advances in mapping and manipulating the epigenome in embryogenesis in mouse models have revealed novel mechanisms regulating genomic imprinting in placental trophoblast, the physiological implications of which are only just beginning to be explored. This review will highlight important recent discoveries and exciting new directions in the study of placental imprinting.
Topics: Animals; DNA Methylation; Female; Genomic Imprinting; Humans; Placenta; Pregnancy; Retroelements
PubMed: 32324732
DOI: 10.1371/journal.pgen.1008709 -
F1000Research 2020Since Barbara McClintock's groundbreaking discovery of mobile DNA sequences some 70 years ago, transposable elements have come to be recognized as important mutagenic... (Review)
Review
Since Barbara McClintock's groundbreaking discovery of mobile DNA sequences some 70 years ago, transposable elements have come to be recognized as important mutagenic agents impacting genome composition, genome evolution, and human health. Transposable elements are a major constituent of prokaryotic and eukaryotic genomes, and the transposition mechanisms enabling transposon proliferation over evolutionary time remain engaging topics for study, suggesting complex interactions with the host, both antagonistic and mutualistic. The impact of transposition is profound, as over 100 human heritable diseases have been attributed to transposon insertions. Transposition can be highly mutagenic, perturbing genome integrity and gene expression in a wide range of organisms. This mutagenic potential has been exploited in the laboratory, where transposons have long been utilized for phenotypic screening and the generation of defined mutant libraries. More recently, barcoding applications and methods for RNA-directed transposition are being used towards new phenotypic screens and studies relevant for gene therapy. Thus, transposable elements are significant in affecting biology both and in the laboratory, and this review will survey advances in understanding the biological role of transposons and relevant laboratory applications of these powerful molecular tools.
Topics: DNA Barcoding, Taxonomic; DNA Transposable Elements; Genetic Therapy; Humans; Mutagenesis, Insertional
PubMed: 32148769
DOI: 10.12688/f1000research.21018.1 -
Cell Mar 2023Accelerating the development of tools for non-model animal research, Dejosez et al. report the generation of induced pluripotent stem cells (iPSCs) from bats using a...
Accelerating the development of tools for non-model animal research, Dejosez et al. report the generation of induced pluripotent stem cells (iPSCs) from bats using a modified Yamanaka protocol. Their study also reveals that bat genomes harbor diverse and unusually abundant endogenous retroviruses (ERVs) that are reactivated during iPSC reprogramming.
Topics: Animals; Chiroptera; Induced Pluripotent Stem Cells; Endogenous Retroviruses
PubMed: 36868212
DOI: 10.1016/j.cell.2023.01.033 -
G3 (Bethesda, Md.) Mar 2023High-quality genome assemblies are characterized by high-sequence contiguity, completeness, and a low error rate, thus providing the basis for a wide array of studies...
High-quality genome assemblies are characterized by high-sequence contiguity, completeness, and a low error rate, thus providing the basis for a wide array of studies focusing on natural species ecology, conservation, evolution, and population genomics. To provide this valuable resource for conservation projects and comparative genomics studies on gyrfalcon (Falco rusticolus), we sequenced and assembled the genome of this species using third-generation sequencing strategies and optical maps. Here, we describe a highly contiguous and complete genome assembly comprising 20 scaffolds and 13 contigs with a total size of 1.193 Gbp, including 8,064 complete Benchmarking Universal Single-Copy Orthologs (BUSCOs) of the total 8,338 BUSCO groups present in the library aves_odb10. Of these BUSCO genes, 96.7% were complete, 96.1% were present as a single copy, and 0.6% were duplicated. Furthermore, 0.8% of BUSCO genes were fragmented and 2.5% (210) were missing. A de novo search for transposable elements (TEs) identified 5,716 TEs that masked 7.61% of the F. rusticolus genome assembly when combined with publicly available TE collections. Long interspersed nuclear elements, in particular, the element Chicken-repeat 1 (CR1), were the most abundant TEs in the F. rusticolus genome. A de novo first-pass gene annotation was performed using 293,349 PacBio Iso-Seq transcripts and 496,195 transcripts derived from the assembly of 42,429,525 Illumina PE RNA-seq reads. In all, 19,602 putative genes, of which 59.31% were functionally characterized and associated with Gene Ontology terms, were annotated. A comparison of the gyrfalcon genome assembly with the publicly available assemblies of the domestic chicken (Gallus gallus), zebra finch (Taeniopygia guttata), and hummingbird (Calypte anna) revealed several genome rearrangements. In particular, nine putative chromosome fusions were identified in the gyrfalcon genome assembly compared with those in the G. gallus genome assembly. This genome assembly, its annotation for TEs and genes, and the comparative analyses presented, complement and strength the base of high-quality genome assemblies and associated resources available for comparative studies focusing on the evolution, ecology, and conservation of Aves.
Topics: Genomics; Molecular Sequence Annotation; Chromosomes; DNA Transposable Elements
PubMed: 36611193
DOI: 10.1093/g3journal/jkad001 -
ELife Nov 2023ZMYM2 is a zinc finger transcriptional regulator that plays a key role in promoting and maintaining cell identity. It has been implicated in several diseases such as...
ZMYM2 is a zinc finger transcriptional regulator that plays a key role in promoting and maintaining cell identity. It has been implicated in several diseases such as congenital anomalies of the kidney where its activity is diminished and cancer where it participates in oncogenic fusion protein events. ZMYM2 is thought to function through promoting transcriptional repression and here we provide more evidence to support this designation. Here we studied ZMYM2 function in human cells and demonstrate that ZMYM2 is part of distinct chromatin-bound complexes including the established LSD1-CoREST-HDAC1 corepressor complex. We also identify new functional and physical interactions with ADNP and TRIM28/KAP1. The ZMYM2-TRIM28 complex forms in a SUMO-dependent manner and is associated with repressive chromatin. ZMYM2 and TRIM28 show strong functional similarity and co-regulate a large number of genes. However, there are no strong links between ZMYM2-TRIM28 binding events and nearby individual gene regulation. Instead, ZMYM2-TRIM28 appears to regulate genes in a more regionally defined manner within TADs where it can directly regulate co-associated retrotransposon expression. We find that different types of ZMYM2 binding complex associate with and regulate distinct subclasses of retrotransposons, with ZMYM2-ADNP complexes at SINEs and ZMYM2-TRIM28 complexes at LTR elements. We propose a model whereby ZMYM2 acts directly through retrotransposon regulation, which may then potentially affect the local chromatin environment and associated coding gene expression.
Topics: Humans; DNA Transposable Elements; Retroelements; Zinc Fingers; Chromatin; Co-Repressor Proteins; DNA-Binding Proteins; Transcription Factors
PubMed: 37934570
DOI: 10.7554/eLife.86669 -
G3 (Bethesda, Md.) Mar 2022Repetitive sequences including transposable elements and transposon-derived fragments account for nearly half of the human genome. While transposition-competent...
Repetitive sequences including transposable elements and transposon-derived fragments account for nearly half of the human genome. While transposition-competent transposable elements must be repressed to maintain genomic stability, mutated and fragmented transposable elements comprising the bulk of repetitive sequences can also contribute to regulation of host gene expression and broader genome organization. Here, we analyzed published ChIP-seq data sets to identify proteins broadly enriched on transposable elements in the human genome. We show 2 of the proteins identified, C2H2 zinc finger-containing proteins ZNF146 (also known as OZF) and ZNF507, are targeted to distinct sites within LINE-1 ORF2 at thousands of locations in the genome. ZNF146 binding sites are found at old and young LINE-1 elements. In contrast, ZNF507 preferentially binds at young LINE-1 sequences correlated to sequence changes in LINE-1 elements at ZNF507's binding site. To gain further insight into ZNF146 and ZNF507 function, we disrupt their expression in HEK293 cells using CRISPR/Cas9 and perform RNA sequencing, finding modest gene expression changes in cells where ZNF507 has been disrupted. We further identify a physical interaction between ZNF507 and PRMT5, suggesting ZNF507 may target arginine methylation activity to LINE-1 sequences.
Topics: Binding Sites; DNA Transposable Elements; Genome, Human; HEK293 Cells; Humans; Kruppel-Like Transcription Factors; Long Interspersed Nucleotide Elements; Protein-Arginine N-Methyltransferases; RNA-Binding Proteins
PubMed: 35100360
DOI: 10.1093/g3journal/jkac002