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B2 and ALU retrotransposons are self-cleaving RNAs whose activity is enhanced by EZH2

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139931 | GEO | 2020/01/31

REPOSITORIES: GEO

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Destabilization of B2 RNA by EZH2 activates the stress response

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.

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Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [ChIP-Seq]

Project description:Alu SINEs are the most numerous frequently occurring transcription units in our genomes and possess sequence competence for transcription by RNA Pol III. However, through poorly understood mechanisms, the Alu RNA levels are maintained at very low levels in normal somatic cells with obvious benefits of low rates of Alu retrotransposition and energy-economical deployment of RNA Pol III to the tRNA genes which share promoter structure and polymerase requirements with Alu SINEs. Using comparative ChIP sequencing, we unveil that a repeat binding protein, CGGBP1, binds to the transcriptional regulatory regions of Alu SINEs thereby impeding Alu transcription by inhibiting RNA Pol III recruitment. We show that this Alu-silencing depends on growth factor stimulation of cells and subsequent tyrosine phosphorylation of CGGBP1. Importantly, CGGBP1 ensures a sequence-specific discriminative inhibition of RNA Pol III activity at Alu promoters, while sparing the structurally similar tRNA promoters. Our data suggest that CGGBP1 contributes to growth-related transcription by preventing the hijacking of RNA Pol III by Alu SINEs. Examination of one DNA binding protein in two different conditions of treatment.

2015-04-29 | E-GEOD-53571 | biostudies-arrayexpress

B2 and ALU retrotransposons are self-cleaving RNAs whose activity is enhanced by EZH2

Project description:B2 and ALU retrotransposons are self-cleaving RNAs whose activity is enhanced by EZH2

| PRJNA587648 | ENA

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [ChIP-Seq]

2015-04-29 | GSE53571 | GEO

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [Affymetrix]

Project description:Alu SINEs are the most numerous frequently occurring transcription units in our genome and possess sequence competence for transcription by RNA Pol III. However, through poorly understood mechanisms, the Alu RNA levels are maintained at very low levels in normal somatic cells with obvious benefits of low rates of Alu retrotransposition and energy-economical deployment of RNA Pol III to the tRNA genes which share promoter structure and polymerase requirements with Alu SINEs. Using comparative ChIP sequencing, we unveil that a repeat binding protein, CGGBP1, binds to the transcriptional regulatory regions of Alu SINEs thereby impeding Alu transcription by inhibiting RNA Pol III recruitment. We show that this Alu-silencing depends on growth factor stimulation of cells and subsequent tyrosine phosphorylation of CGGBP1. Importantly, CGGBP1 ensures a sequence-specific discriminative inhibition of RNA Pol III activity at Alu promoters, while sparing the structurally similar tRNA promoters. Our data suggest that CGGBP1 contributes to growth-related transcription by preventing the hijacking of RNA Pol III by Alu SINEs. This study was used to find out the effect of CGGBP1 on serum-induced changes in gene expression and effect of serum on gene expression regulation by CGGBP1. Gene expression profiling of normal human fibroblasts under 4 different experimental perturbations: serum starvation or serum stimulation and CGGBP1 depletion or normal CGGBP1 levels.

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Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [Affymetrix]

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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.

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Genome-wide maps of histone H3K9 acetylation in the mouse strains C57BL/6J, MSM/Ms, and their F1 hybrids

Project description:More than one million copies of short interspersed elements (SINEs), a class of retrotransposons, are present in the mammalian genomes, particularly within gene-rich genomic regions. Evidence has accumulated that ancient SINE sequences have acquired new binding sites for transcription factors (TFs) through multiple mutations following retrotransposition, and as a result have rewired the host regulatory network during the course of evolution. However, it remains unclear whether currently active SINEs contribute to the expansion of TF binding sites. To study the mobility, expression, and function of SINE copies, we first identified about 2,000 insertional polymorphisms of B1 and B2 SINE families within Mus musculus. Using a novel RNA sequencing method developed here, we detected the expression of SINEs in testes at both the subfamily and genomic copy levels: the vast majority of B1 RNAs originated from evolutionarily young subfamilies, whereas B2 RNAs contained transcripts from both young and old subfamilies. DNA methylation and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses revealed that polymorphic B2 insertions served as a chromatin boundary element inhibiting the expansion of DNA hypomethylated and histone hyperacetylated regions, and decreased the expression of neighboring genes. Moreover, a total of > 100 polymorphic B2 insertions were bound by CTCF, a well-known chromatin boundary protein. These results suggest that the currently active B2 copies are mobile chromatin boundary elements that can modulate gene expression level, and are likely involved in epigenomic and phenotypic diversification of the mouse species.

2021-05-26 | GSE156316 | GEO

Transcriptome-scale analysis for RNAs of medium length, designated as melRNA-seq

Project description:More than one million copies of short interspersed elements (SINEs), a class of retrotransposons, are present in the mammalian genomes, particularly within gene-rich genomic regions. Evidence has accumulated that ancient SINE sequences have acquired new binding sites for transcription factors (TFs) through multiple mutations following retrotransposition, and as a result have rewired the host regulatory network during the course of evolution. However, it remains unclear whether currently active SINEs contribute to the expansion of TF binding sites. To study the mobility, expression, and function of SINE copies, we first identified about 2,000 insertional polymorphisms of SINE B1 and B2 families within Mus musculus. Using a novel RNA sequencing method developed here, we detected the expression of SINEs in male germ cells at both the subfamily and genomic copy levels: the vast majority of B1 RNAs originated from evolutionarily young subfamilies, whereas B2 RNAs originated from both young and old subfamilies. DNA methylation and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses in liver revealed that polymorphic B2 insertions served as a chromatin boundary element inhibiting the expansion of DNA hypomethylated and histone hyperacetylated regions, and decreased the expression of neighboring genes. Moreover, genomic B2 copies were enriched at the boundary of ChIP-seq peaks of various histone modifications. A total of > 100 polymorphic B2 insertions, together with >10,000 non-polymorphic B2 copies, were bound by CTCF, a well-known chromatin boundary protein. These results suggest that the currently active B2 copies are mobile chromatin boundary elements that can modulate gene expression level, and are likely involved in epigenomic and phenotypic diversification of the mouse species.

2021-05-26 | GSE156315 | GEO

SINE transcription by RNA polymerase III is suppressed by histone methylation but not DNA methylation

Project description:Nearly half the human genome is comprised of repetitive DNA, including short interspersed nuclear elements (SINEs) such as Alu. SINEs spread by retrotransposition, which requires their transcripts to be copied into DNA and then inserted into new chromosomal sites. This can lead to genetic damage through insertional mutagenesis and through chromosomal rearrangements between nonallelic SINEs at distinct loci. SINE DNA is heavily methylated and this is thought to suppress its accessibility and transcription, thereby protecting against retrotransposition. However, we provide several lines of evidence that methylated SINE DNA is occupied genome-wide by RNA polymerase III, including the use of high-throughput bisulphite sequencing of ChIP DNA (ChIP-BS-Seq). Loss of DNA methylation has little effect on expression of SINEs or their accessibility to transcription machinery. We present evidence that methylation of histones rather than DNA plays a dominant role in suppressing SINE expression.

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