B2 and ALU retrotransposons are self-cleaving RNAs whose activity is enhanced by EZH2
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PROVIDER: PRJNA587648 | ENA |
REPOSITORIES: ENA
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Project description:More than 98% of the mammalian genome is noncoding and approximately half is made up of transposable elements. One of the most abundant is the short interspersed nuclear elements (SINE). Among the million copies of SINEs, B2 accounts for ~350,000 in the mouse genome and have garnered special interest because of emerging roles in gene regulation. Our recent work demonstrated that B2 RNA normally binds stress genes to retard transcription elongation. Though epigenetically silenced, B2s become massively upregulated during thermal stress. Specifically, an interaction between B2 RNA and the Polycomb protein, EZH2, results in cleavage of B2 RNA, release of B2 RNA from RNA Polymerase II, and activation of the stress genes. Although an established RNA-binding protein and histone methyltransferase, EZH2 is not known to be a nuclease. Here, we provide evidence for the surprising conclusion that B2 is a self-cleaving RNA. Contact with EZH2 accelerates cleavage rate by >100-fold, suggesting that EZH2 may assist cleavage as an RNA chaperone. Modification-interference analysis demonstrate that phosphorothioate changes at A and C nucleotides can substitute for EZH2’s function. B2 mutagenesis indicate that nucleotides around positions 45-55 and 100-101 are critical for cleavage reaction. Finally, we demonstrate that another family of SINEs, the ALU elements produce also a self-cleaving RNA. ALUs are intrinsically more auto-reactive than B2s. We propose that the B2/ALU SINEs are a new class of ribozymes whose activity is accelerated by EZH2.
2020-01-31 | GSE139931 | GEO
Project description: Not available
| S-EPMC6955291 | biostudies-literature
Project description:Our work sheds light on the metabolism of RNA transcripts derived from genomic Alu repeats. Since it is unclear whether Alu elements are transcribed mainly by RNA polymerase II or III, we conducted a transcription shutoff experiment and metabolic RNA labeling. We find that Alu transcripts are as stable as mRNAs and originate in part from RNA polymerase II. Furthermore, we use the de Bruijn graph of all Alu sequences to discover sequence features that match transcription factor binding motifs.
2022-04-01 | GSE185485 | GEO
Project description:More than 98% of the mammalian genome is noncoding and interspersed transposable elements account for ~50% of noncoding space. Here, we demonstrate that a specific interaction between the Polycomb protein, EZH2, and RNA made from B2 SINE retrotransposons controls stress-responsive genes in mouse cells. In the heat shock model, B2 RNA binds stress genes and suppresses their transcription. Upon stress, EZH2 is recruited and triggers cleavage of B2 RNA. B2 degradation in turn upregulates stress genes. Evidence indicates that B2 RNA operates as "speed bumps" against advancement of RNA Polymerase II and temperature stress releases the brakes on transcriptional elongation. These data attribute a new function to EZH2 that is independent of its histone methyltransferase activity and reconcile how EZH2 can be associated with both gene repression and activation. Our study reveals that EZH2 and B2 together control activation of a large network of genes involved in thermal stress.
2016-12-19 | GSE82255 | GEO
Project description:RNA transcription and degradation of Alu retrotransposons depends on sequence features and evolutionary history
| PRJNA769185 | ENA
Project description:DNA methylation is the major repression mechanism for human retrotransposons, such as the Alu family. Here, we have derived methylation levels regarding 5238 loci belonging to two Alu subfamilies, AluYa5 and AluYb8, using High-Throughput Targeted Repeat Element Bisulfite Sequencing (HT-TREBS). The results indicate that ~90% of loci are repressed by high methylation levels. Of the remaining loci, many of these hypomethylated elements are found near gene promoters and show high levels of DNA methylation variation. We have characterized this variation in the context of tumorigenesis and inter-individual differences. Comparison of a primary breast tumor and its matched normal tissue revealed early DNA methylation changes in ~1% of AluYb8 elements in response to tumorigenesis. At the same time, AluYa5/Yb8 elements proximal to promoters also showed differences in methylation of up to one order of magnitude even between normal individuals. Overall, the current study demonstrates that early loss of methylation occurs during tumorigenesis in a subset of young Alu elements, suggesting their potential clinical relevance. However, techniques such as deep-bisulfite-sequencing of individual loci using HT-TREBS are required to distinguish clinically relevant loci from the background observed for AluYa5/Yb8 elements in general with regard to high levels of inter-individual variation in DNA methylation. HT-TREBS has been used with the Ion Torrent PGM platform to analyze the DNA methylation of 5238 AluYa5/Yb8 elements in a locus-specific manner in human skin-derived fibroblast cells, and a matched normal breast and primary tumor
2016-10-27 | E-GEOD-74420 | biostudies-arrayexpress
Project description:Short interspersed nuclear elements (SINEs) are retrotransposons evolutionarily derived from endogenous RNA Polymerase III RNAs. Though SINE elements have undergone exaptation into gene regulatory elements, how transcribed SINE RNA impacts transcriptional and post-transcriptional regulation is largely unknown. This is partly due to a lack of information regarding which of the loci have transcriptional potential. Here, we present an approach (short interspersed nuclear element sequencing, SINE-seq), which selectively profiles RNA Polymerase III-derived SINE RNA, thereby identifying transcriptionally active SINE loci. Applying SINE-seq to monitor murine B2 SINE expression during a gammaherpesvirus infection revealed transcription from 28,270 SINE loci, with ~50% of active SINE elements residing within annotated RNA Polymerase II loci. Furthermore, B2 RNA can form intermolecular RNA-RNA interactions with complementary mRNAs, leading to nuclear retention of the targeted mRNA via a mechanism involving p54nrb. These findings illuminate a pathway for the selective regulation of mRNA export during stress via retrotransposon activation.
2016-10-31 | GSE85518 | GEO
Project description:Alu retrotransposons, forming the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their bulk expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus, by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase and of the YAP1 and FOS transcription factors. The physical interaction of e1a with the chromatin remodeler EP400 turned out to be critical for Alu derepression, and upstream enrichment of EP400 was found to commonly demarcate expression-prone Alus. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, mediated by e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenovirus.
2024-03-31 | GSE208716 | GEO
Project description:Alu retrotransposons, forming the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their bulk expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus, by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase and of the YAP1 and FOS transcription factors. The physical interaction of e1a with the chromatin remodeler EP400 turned out to be critical for Alu derepression, and upstream enrichment of EP400 was found to commonly demarcate expression-prone Alus. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, mediated by e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenovirus.
2024-03-31 | GSE208685 | GEO
Project description:Alu retroelements, whose retrotransposition requires prior transcription by RNA polymerase III to generate Alu RNAs, represent the most numerous non-coding RNA (ncRNA) gene family in the human genome. Alu transcription is generally kept to extremely low levels by tight epigenetic silencing, but it has been reported to increase under different types of cell perturbation, such as viral infection and cancer. Alu RNAs, being able to act as gene expression regulators, might be directly involved in the mechanisms determining cellular behavior in such perturbed states. To directly address the regulatory potential of Alu RNAs, we generated IMR90 fibroblast and HeLa cell lines stably overexpressing two slightly different Alu RNAs, and analyzed genome-wide the expression changes of protein-coding genes through RNA-Sequencing. Among the genes that were upregulated or downregulated in response to Alu overexpression in IMR90, but not in HeLa cells, we found a highly significant enrichment of pathways involved in cell cycle progression and mitotic entry, including increased expression of the key cell cycle transcriptional regulator FOXM1 and several FOXM1-regulated genes. Overall, the results of our analysis suggest that increased Alu RNA favors cell cycle progression thus contributing to enable sustained cell proliferation which is an important factor of cancer development and progression.
2019-06-21 | GSE133078 | GEO