Human cytomegalovirus hijacks L1 retrotransposon to fuel its heterogeneity
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PROVIDER: PRJNA897076 | ENA |
REPOSITORIES: ENA
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Project description:Human Cytomegalovirus (HCMV) causes severe morbidity and mortality in an immune-compromised or immune-naïve host. Among DNA viruses, the genetic diversity of HCMV is unexpectedly high and comparable to those of RNA viruses, which hinders the development of effective vaccines and causes the emergence of antiviral resistance. However, little is known about how HCMV acquires genetic variation. Here, we propose an evolution strategy of HCMV, that exploits host “jumping DNA” L1 retrotransposon as a mutagen. We found that HCMV infection switches on L1 expression by upregulating transcription factors YY1 and RUNX3. Furthermore, HCMV DNA processivity factor, UL44 recruits L1 ribonucleoproteins to viral replication compartments and induces DNA damage to its genome. Deep-sequencing analysis of cultured HCMV genome revealed that L1 retrotransposon facilitates mutation burden on the viral genome. Indeed, laboratory adaptation of HCMV to fibroblasts is only observed upon active L1 expression. These findings demonstrate the evolution mechanism and molecular insights of how HCMV acquires genetic fitness by the hijacking of host L1 retrotransposon.
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Project description:We used ATLAS-seq-neo to map the sites of integration of an engineered LINE-1 (L1) retrotransposon into the genome of HeLa S3 cells. In brief, we transfected cells with a plasmid-borne L1.3 element carrying a NeoR-based retrotransposition cassette. Cells were selected by G418 and used to prepare ATLAS-seq-neo libraries. Each sample corresponds to an independent transfection and pool of G418-resistant cells. ATLAS-seq-neo relies on the random mechanical fragmentation of the genomic DNA to ensure high-coverage, ligation of adapter sequences, suppression PCR-amplification of the 3' end L1 junction with its flanking genomic sequence, and Ion Torrent sequencing using single-end 400 bp read chemistry. The primer used for suppression PCR specifically targets the engineered element and not endogenous copies as in the original ATLAS-seq protocol (Philippe et al. eLife 2016).
2019-04-04 | E-MTAB-6933 | biostudies-arrayexpress
Project description:The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We have characterized structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be further used to better understand the life cycle of this element and its impact on human health.
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Project description:Genetic parasites, including viruses and transposons, exploit components from the host for their own replication. However, little is known about virus-transposon interactions within host cells. Here, we discover a strategy where human cytomegalovirus (HCMV) hijacks L1 retrotransposon encoded protein during its replication cycle. HCMV infection upregulates L1 expression by enhancing both the expression of L1-activating transcription factors, YY1 and RUNX3, and the chromatin accessibility of L1 promoter regions. Increased L1 expression, in turn, promotes HCMV replicative fitness. Affinity proteomics reveals UL44, HCMV DNA polymerase subunit, as the most abundant viral binding protein of the L1 ribonucleoprotein (RNP) complex. UL44 directly interacts with L1 ORF2p, inducing DNA damage responses in replicating HCMV compartments. While increased L1-induced mutagenesis is not observed in HCMV for genetic adaptation, the interplay between UL44 and ORF2p accelerates viral DNA replication by alleviating replication stress. Our findings shed light on how HCMV exploits host retrotransposons for enhanced viral fitness.
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Project description:We used ATLAS-seq-neo to map the sites of integration of an engineered LINE-1 (L1) retrotransposon into the genome of HeLa S3 cells. In brief, we transfected cells with a plasmid-borne L1.3 element carrying a neomycin-resistance-based retrotransposition cassette, as well as a hygromycin-resistance cassette on the plasmid backbone. For this set of experiments, cells were only selected for transfection (hygromycin) but not for retrotransposition (neomycin). Then we prepared ATLAS-seq-neo libraries. Each sample corresponds to an independent transfection and pool of hygromycin-resistant cells. ATLAS-seq-neo relies on the random mechanical fragmentation of the genomic DNA to ensure high-coverage, ligation of adapter sequences, suppression PCR-amplification of the 3' end L1 junction with its flanking genomic sequence, and Ion Torrent sequencing using single-end 400 bp read chemistry. The primer used for suppression PCR specifically targets the engineered element and not endogenous copies as in the original ATLAS-seq protocol (Philippe et al. eLife 2016). For some libraries, the linker-ligated genomic DNA was digested with BamHI, which cuts downstream of L1 polyA site in the plasmid backbone, to limit amplification from the plasmid and enrich for retrotransposition-mediated insertion events into the genomic DNA.
2019-04-03 | E-MTAB-7644 | biostudies-arrayexpress
Project description:Fuel ethanol is now considered a global energy commodity that is fully competitive with gasoline. We have determined genome copy number differences that are common to five industrially important fuel ethanol yeast strains responsible for the production of billions of gallons of fuel ethanol per year from sugarcane. The fuel strains used were CAT1, BG1, PE2, SA1, and VR1 (note that two independent isolates were analyzed, denoted by "-1" and "-2"). These array-CGH data were compared with array-CGH data from nine other non-fuel industrial yeasts: An ale brewing strain ("Sc-ale"), four wine strains (GSY2A, GSY3A, GSY10A, GSY11B), and 4 bakers' yeast strains (GSY149, GSY150, GSY154, GSY155). Our results reveal significant amplifications of the telomeric SNO and SNZ genes only in the fuel strains, whose protein products are involved in the biosynthesis of vitamins B6 (pyridoxine) and B1 (thiamin). We show that these amplifications allow these yeasts to grow efficiently, especially at high sugar concentrations, regardless of the presence or absence of either of the two vitamins. Our results reveal important genetic adaptations that have been selected for in the industrial environment, which may be required for the efficient fermentation of biomass-derived sugars from other renewable feedstocks. A strain or line experiment design type assays differences between multiple strains, cultivars, serovars, isolates, lines from organisms of a single species. Strain Name: fuel strains used for aCGH Strain_or_line_design
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