The study of somatic LINE1 activity in cancers
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ABSTRACT:
PROVIDER: PRJNA1210008 | ENA |
REPOSITORIES: ENA
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Project description:the study of somatic LINE1 activity in cancers
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Project description:LINE1 TGS mechanism mediated by SETDB1-AGO2 complex in human somatic cells
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Project description:p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germ line tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5’UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.
2020-12-01 | GSE159134 | GEO
Project description:In this study, we report the protective effect of LINE1 intervention on vascular calcification. To elucidate the molecular mechanisms underlying the protective role of LINE1 inhibition, we employed RNA sequencing to identify gene expression changes under LINE1 suppression conditions. Our findings provide insights into the pathways involved in modulating vascular calcification and highlight LINE1 as a potential therapeutic target.
2025-07-15 | GSE279148 | GEO
Project description:Somatic Mutation in Normal Bladder Study
| PRJNA1278817 | ENA
Project description:Somatic Mutation in Normal Bladder Study
| PRJNA1278818 | ENA
Project description:LINE1s are abundant retroelements comprising 17% of human genome. Naturally, genomic LINE1s are tightly repressed by epigenetic mechanism; however, if relieved, they can be detrimental to genome stability by their transposition capability. So, a supervising mechanism that quickly re-represses the leaky LINE1s is demanded. Here we show that de-repressed LINE1s generate small RNAs, L1-siRNAs, which SETDB1 and AGO2 recognize, then move into searching for a transcript with sequence complementarity, and ultimately re-install a repression mechanism at LINE1 5’-untranslated region (5’UTR) by depositing trimethyl-H3K9 (H3K9me3). Immunoprecipitation (IP) results showed that SETDB1, AGO2, and L1-siRNA bound to each other and Chromatin-IP-seq and small-RNA-seq results demonstrated that they sat at the same locus within the 5’UTR. SETDB1, AGO2, and L1-siRNA all were necessary for LINE1 repression, particularly the evolutionary young and transposition-competent families such as L1HS/L1PA1 and L1PA2. KAP1, which frequently partners with SETDB1 for silencing local chromatin, was dispensible for the repression of young L1PAs. Our findings indicate that, as a surveillance mechanism, the L1-siRNA-triggered, SETDB1-AGO2-effected repair of epigenetic errors at the 5’UTR establishes a homeostatic re-repression mechanism on inadvertently de-repressed LINE1 copies over the genome.
2023-08-21 | GSE203287 | GEO
Project description:LINE1s are abundant retroelements comprising 17% of human genome. Naturally, genomic LINE1s are tightly repressed by epigenetic mechanism; however, if relieved, they can be detrimental to genome stability by their transposition capability. So, a supervising mechanism that quickly re-represses the leaky LINE1s is demanded. Here we show that de-repressed LINE1s generate small RNAs, L1-siRNAs, which SETDB1 and AGO2 recognize, then move into searching for a transcript with sequence complementarity, and ultimately re-install a repression mechanism at LINE1 5’-untranslated region (5’UTR) by depositing trimethyl-H3K9 (H3K9me3). Immunoprecipitation (IP) results showed that SETDB1, AGO2, and L1-siRNA bound to each other and Chromatin-IP-seq and small-RNA-seq results demonstrated that they sat at the same locus within the 5’UTR. SETDB1, AGO2, and L1-siRNA all were necessary for LINE1 repression, particularly the evolutionary young and transposition-competent families such as L1HS/L1PA1 and L1PA2. KAP1, which frequently partners with SETDB1 for silencing local chromatin, was dispensible for the repression of young L1PAs. Our findings indicate that, as a surveillance mechanism, the L1-siRNA-triggered, SETDB1-AGO2-effected repair of epigenetic errors at the 5’UTR establishes a homeostatic re-repression mechanism on inadvertently de-repressed LINE1 copies over the genome.
2023-08-21 | GSE203286 | GEO
Project description:LINE1s are abundant retroelements comprising 17% of human genome. Naturally, genomic LINE1s are tightly repressed by epigenetic mechanism; however, if relieved, they can be detrimental to genome stability by their transposition capability. So, a supervising mechanism that quickly re-represses the leaky LINE1s is demanded. Here we show that de-repressed LINE1s generate small RNAs, L1-siRNAs, which SETDB1 and AGO2 recognize, then move into searching for a transcript with sequence complementarity, and ultimately re-install a repression mechanism at LINE1 5’-untranslated region (5’UTR) by depositing trimethyl-H3K9 (H3K9me3). Immunoprecipitation (IP) results showed that SETDB1, AGO2, and L1-siRNA bound to each other and Chromatin-IP-seq and small-RNA-seq results demonstrated that they sat at the same locus within the 5’UTR. SETDB1, AGO2, and L1-siRNA all were necessary for LINE1 repression, particularly the evolutionary young and transposition-competent families such as L1HS/L1PA1 and L1PA2. KAP1, which frequently partners with SETDB1 for silencing local chromatin, was dispensible for the repression of young L1PAs. Our findings indicate that, as a surveillance mechanism, the L1-siRNA-triggered, SETDB1-AGO2-effected repair of epigenetic errors at the 5’UTR establishes a homeostatic re-repression mechanism on inadvertently de-repressed LINE1 copies over the genome.
2023-08-21 | GSE203285 | GEO
Project description:LINE1 TGS mechanism mediated by SETDB1-AGO2 complex in human somatic cells [MBD-seq]
| PRJNA839361 | ENA