Impaired function of rDNA transcription initiation machinery leads to derepression of ribosomal genes with insertions of R2 retrotransposon
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ABSTRACT:
PROVIDER: PRJNA758906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15668748.fastq.gz | Fastqsanger.gz | |||
| SRR15668749.fastq.gz | Fastqsanger.gz | |||
| SRR15668750.fastq.gz | Fastqsanger.gz | |||
| SRR15668751.fastq.gz | Fastqsanger.gz | |||
| SRR15668752_1.fastq.gz | Fastqsanger.gz |
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Project description:Eukaryotic genomes harbor hundreds of rRNA genes, many of which are transcriptionally silent. However, little is known about selective regulation of individual rDNA units. In Drosophila melanogaster, some rDNA repeats contain insertions of the R2 retrotransposon, which is capable to be transcribed only as part of pre-rRNA molecules. rDNA units with R2 insertions are usually inactivated, although R2 expression may be beneficial in cells with decreased rDNA copy number. Here we found that R2-inserted rDNA units are enriched with HP1a and H3K9me3 repressive mark, whereas disruption of the heterochromatin components slightly affects their silencing in ovarian germ cells. Surprisingly, we observed a dramatic upregulation of R2-inserted rRNA genes in ovaries lacking Udd (Under-developed) or other subunits (TAF1b and ТAF1c-like) of the SL1-like complex, which is homologues to mammalian Selective factor 1 (SL1) involved in rDNA transcription initiation. Derepression of rRNA genes with R2 insertions was accompanied by a reduction of H3K9me3 and HP1a enrichment. We suggest that the impairment of the SL1-like complex affects a mechanism of selective activation of intact rDNA units which competes with heterochromatin formation. We also propose that R2 derepression may serve as an adaptive response to compromised rRNA synthesis.
2021-10-09 | GSE183035 | GEO
Project description:Eukaryotic genomes harbor hundreds of rRNA genes, many of which are transcriptionally silent. However, little is known about selective regulation of individual rDNA units. In Drosophila melanogaster, some rDNA repeats contain insertions of the R2 retrotransposon, which is capable to be transcribed only as part of pre-rRNA molecules. rDNA units with R2 insertions are usually inactivated, although R2 expression may be beneficial in cells with decreased rDNA copy number. Here we found that R2-inserted rDNA units are enriched with HP1a and H3K9me3 repressive mark, whereas disruption of the heterochromatin components slightly affects their silencing in ovarian germ cells. Surprisingly, we observed a dramatic upregulation of R2-inserted rRNA genes in ovaries lacking Udd (Under-developed) or other subunits (TAF1b and TAF1c-like) of the SL1-like complex, which is homologues to mammalian Selective factor 1 (SL1) involved in rDNA transcription initiation. Derepression of rRNA genes with R2 insertions was accompanied by a reduction of H3K9me3 and HP1a enrichment. We suggest that the impairment of the SL1-like complex affects a mechanism of selective activation of intact rDNA units which competes with heterochromatin formation. We also propose that R2 derepression may serve as an adaptive response to compromised rRNA synthesis.
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Project description:The establishment of distinct transcription programs during development is controlled by transcription factor networks acting in specific chromatin environments. The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous Murine Leukemia Virus (MLV) copies. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development critically depends on the proper repression of retrotransposon sequences through Setdb1. Transcriptomic and chromatin analysis of control and Setdb1-deficient pro-B cells
2016-07-20 | E-GEOD-77636 | biostudies-arrayexpress
Project description:The establishment of distinct transcription programs during development is controlled by transcription factor networks acting in specific chromatin environments. The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous Murine Leukemia Virus (MLV) copies. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development critically depends on the proper repression of retrotransposon sequences through Setdb1.
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Project description:Frequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites
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Project description:CRISPR/Cas9-based genome editing has revolutionized experimental molecular biology and entered the clinical world for targeted gene therapy. Identifying DNA modifications occurring at CRISPR/Cas9 target sites is critical to determine efficiency and safety of editing tools. Here we show that insertions of LINE-1 (L1) retrotransposons can occur frequently at CRISPR/Cas9 editing sites. Together with PolyA-seq and an improved amplicon sequencing, we characterize more than 2,500 de novo L1 insertions at multiple CRISPR/Cas9 editing sites in HEK293T, HeLa and U2OS cells. These L1 retrotransposition events exploit CRISPR/Cas9-induced DSB formation and require L1 RT activity. Importantly, de novo L1 insertions are rare during genome editing by prime editors (PE), cytidine or adenine base editors (CBE or ABE), consistent with their reduced DSB formation. These data demonstrate that insertions of retrotransposons might be a potential outcome of CRISPR/Cas9 genome editing and provide further evidence on the safety of different CRISPR-based editing tools.
2022-06-07 | GSE178440 | GEO
Project description:Inhibition of EZH2 causes retrotransposon derepression and immune activation in porcine lung alveolar macrophages.
| PRJNA914630 | ENA
Project description:Alveolar macrophages (AMs) form the first defense line against a variety of respiratory pathogens, and their immune response has profound impact on the outcome of respiratory infection. It is of critical importance to clarify the immune regulation in AMs. Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attentions about their roles in immune regulation. However, the molecular mechanism underlying the immune regulation role of EZH2 in AMs remains largely unclear. Using porcine 3D4/21 alveolar macrophage cells as model, this study combined transcriptomic and epigenomic techniques to decipher the molecular function of EZH2 in AMs. Transcriptomic comparison revealed that inhibition of EZH2 in AMs causes transcriptional activation of dozens of immune genes which indicates an enhanced antiviral state, and as expected, we found that the infection of influenza A viruses can be remarkably affected. Interestingly, about one hundred families of transposable elements, particularly LTRs/ERVs and LINEs which belong to retrotransposons, get derepressed after EZH2 inhibition. Given that derepression of ERVs promotes innate immune activation in many tumors through the “viral mimicry” mechanism, the derepression of retrotransposon in AMs may also contribute to the coincided immune activation after EZH2 inhibition. Overall, this study improves the mechanistical understanding on the EZH2-dependent immune regulation in AMs and provides novel insights for the epigenetic regulation of retrotransposons in pigs.
2023-02-15 | GSE221476 | GEO
Project description:Alveolar macrophages (AMs) form the first defense line against a variety of respiratory pathogens, and their immune response has profound impact on the outcome of respiratory infection. It is of critical importance to clarify the immune regulation in AMs. Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attentions about their roles in immune regulation. However, the molecular mechanism underlying the immune regulation role of EZH2 in AMs remains largely unclear. Using porcine 3D4/21 alveolar macrophage cells as model, this study combined transcriptomic and epigenomic techniques to decipher the molecular function of EZH2 in AMs. Transcriptomic comparison revealed that inhibition of EZH2 in AMs causes transcriptional activation of dozens of immune genes which indicates an enhanced antiviral state, and as expected, we found that the infection of influenza A viruses can be remarkably affected. Interestingly, about one hundred families of transposable elements, particularly LTRs/ERVs and LINEs which belong to retrotransposons, get derepressed after EZH2 inhibition. Given that derepression of ERVs promotes innate immune activation in many tumors through the “viral mimicry” mechanism, the derepression of retrotransposon in AMs may also contribute to the coincided immune activation after EZH2 inhibition. Overall, this study improves the mechanistical understanding on the EZH2-dependent immune regulation in AMs and provides novel insights for the epigenetic regulation of retrotransposons in pigs.
2023-02-15 | GSE221478 | GEO
Project description:Alveolar macrophages (AMs) form the first defense line against a variety of respiratory pathogens, and their immune response has profound impact on the outcome of respiratory infection. It is of critical importance to clarify the immune regulation in AMs. Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attentions about their roles in immune regulation. However, the molecular mechanism underlying the immune regulation role of EZH2 in AMs remains largely unclear. Using porcine 3D4/21 alveolar macrophage cells as model, this study combined transcriptomic and epigenomic techniques to decipher the molecular function of EZH2 in AMs. Transcriptomic comparison revealed that inhibition of EZH2 in AMs causes transcriptional activation of dozens of immune genes which indicates an enhanced antiviral state, and as expected, we found that the infection of influenza A viruses can be remarkably affected. Interestingly, about one hundred families of transposable elements, particularly LTRs/ERVs and LINEs which belong to retrotransposons, get derepressed after EZH2 inhibition. Given that derepression of ERVs promotes innate immune activation in many tumors through the “viral mimicry” mechanism, the derepression of retrotransposon in AMs may also contribute to the coincided immune activation after EZH2 inhibition. Overall, this study improves the mechanistical understanding on the EZH2-dependent immune regulation in AMs and provides novel insights for the epigenetic regulation of retrotransposons in pigs.
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