Functional characterization of the TERRA transcriptome at damaged telomeres
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Julien Delafontaine
PROVIDER: E-GEOD-56727 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:We characterize the TERRA transcriptome at normal and TRF2-depleted telomeres by RNA-seq and we demonstrate that TERRA upregulation is occurring at all transcribed telomeres upon depletion of TRF2.
2014-10-31 | GSE56727 | GEO
Project description:Telomere binding factor 2 (TRF2), is a protein that plays a major role in the maintenance of telomere integrity. In mitotic normal and transformed cells, TRF2 inhibition triggers a rapid telomere DNA damage response that results in cell senescence or apoptosis. Here we provide evidence that TRF2 plays a role suppressing neuronal differentiation. TRF2 interacts with the RE1-silencing transcription factor (REST) in nuclear PML protein-containing compartments of neuronal cells in vivo. Inhibition of TRF2 function with a dominant-negative form of TRF2 elicits a telomeric DNA damage response, and disrupts the TRF2-REST complex resulting in proteasomal degradation of REST. Overexpression of REST impairs the ability of DN-TRF2 to induce neuronal differentiation, indicating that enhanced degradation of REST is sufficient to account for the differentiation-inducing effect of DN-TRF2. REST degradation derepresses RE1-regulated genes (L1CAM, BDNF, b3-tubulin, syntaxin and others) resulting in morphological and functional differentiation of neurons. Our findings identify a novel interaction between the telomeric protein TRF2 and REST which regulates the molecular differentiation program of neurons. Keywords: transfection and molecular inhibition
2007-07-01 | GSE6983 | GEO
Project description:TRF2 is a paralogue of TATA-box binding protein (TBP) with highest expression in testis. Although Trf2 inactivation in mice leads to arrested spermatogenesis, there is no direct evidence that Trf2 is recruited to chromatin to directly regulate gene expression. We used genetically modified mice where endogenous Trf2 has been modified to carry a TAP-TAG to perform ChIP-reChIP followed by deep sequencing. We found that Trf2 is recruited to all active promoters as a subunit of TFIIA/ALF complex together with TBP. To assess the effect of Trf2 inactivation on gene expression we performed RNA-seq on WT and Trf2-/- testes at 21 days of age when haploid cell gene expression is activated.
2016-08-31 | GSE79602 | GEO
Project description:Telomeres are the nucleoprotein complexes located at the tips of eukaryotic chromosomes, composed of repetitive DNA (TTAGGG in vertebrates), and coated by a set of proteins collectively known as the shelterin complex. Dysfunctional telomeres resemble DSBs and they have been observed during ageing and cancer and a number of pathological conditions. Apart from telomeric repeat-containing RNA (TERRA), a non-coding UUAGGG-rich transcript starting from promoters located in the subtelomeric region, in mammals no other transcripts at telomeres have been characterized so far. Here we show that in mammals telomere dysfunction (analysed using TRF2+/- and TRF2-/- mouse embryonic fibroblasts) induces the transcription of telomeric DDRNAs (tDDRNAs) from both DNA strands. To characterize the length and sequence of tDDRNAs, we devised and employed an innovative method for target enrichment of RNA, based on in solution capture of low abundance small RNA species followed by next generation sequencing, developed in our laboratories. By this approach, we observed that telomere deprotection induced the accumulation of small RNA species generated from the transcription of both telomere strands and including the expected DDRNA size range products. Importantly, 20-23 nucleotide RNAs displayed a base bias at both 5’ and 3’ ends significantly different from the telomeric locus suggesting a regulated processing.
2017-05-10 | GSE86964 | GEO
Project description:Background: The Telomeric Repeat binding Factor 2 (TRF2), a key protein involved in telomere integrity, is over-expressed in several human cancers and promotes tumor formation and progression. Recently, TRF2 has been also found outside telomeres where it can affect gene expression. Here we provide evidence that TRF2 is able to modulate the expression of microRNAs (miRNAs), small non-coding RNAs altered in human tumors. Among the miRNAs regulated by TRF2, we focused on the miR-193b-3p, an oncomiRNA that positively correlates with TRF2 expression in human colorectal cancer patients. At the mechanistic level, the control of miR-193b-3p expression requires the cooperative activity between TRF2 and the chromatin organization factor CTCF. We found that CTCF physically interacts with TRF2, thus driving the proper positioning of TRF2 on a binding site located upstream the miR-193b-3p host-gene. The binding of TRF2 on the identified region is necessary for promoting the expression of miR-193b3p which, in turn, inhibits the translation of the onco-suppressive methyltransferase SUV39H1 and promotes tumor cell proliferation. The translational relevance of the oncogenic properties of miR-193b-3p was confirmed in patients, in whom the association between TRF2 and miR-193b-3p has a prognostic value.
2022-03-17 | GSE186022 | GEO
Project description:TRF2 is a paralogue of TATA-box binding protein (TBP) with highest expression in testis. Although Trf2 inactivation in mice leads to arrested spermatogenesis, there is no direct evidence that Trf2 is recruited to chromatin to directly regulate gene expression. We used genetically modified mice where endogenous Trf2 has been modified to carry a TAP-TAG to perform ChIP-reChIP followed by deep sequencing. We found that Trf2 is recruited to all active promoters as a subunit of TFIIA/ALF complex together with TBP.
2016-08-31 | GSE79601 | GEO
Project description:We report the TRF2 binding sites in post mitotic mammalian cells under TRF2 (protein level) modulation. By obtaining sequences from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of differentiated muscle cells (myotubes). Importantly we find that TRF2 levels are correlated with age (R= 0.60) making our results of importance in regards of the changes that occur in the chromatin landscape upon aging. We found multiple TRF2 binding sites that are conserved across cell types (Young et al., 2008, Simonet et al., 2011) highlighting the central role of TRF2 as a key chromatin modifier and gene regulator.
2017-10-17 | GSE88983 | GEO
Project description:Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.
2017-06-29 | GSE79180 | GEO
Project description:Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a nontelomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current RNA-binding model of FMRP, we show that FMRP occupies the GAR domain of TRF2-S protein to block the assembly of TRF2-S-mRNA complexes. Overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons, and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release.
2015-11-06 | GSE72887 | GEO
Project description:The genome consists of non-B-DNA structures such as G-quadruplexes (G4) that are involved in the regulation of genome stability and transcription. Telomeric-repeat containing RNA (TERRA) is capable of folding into G-quadruplex and interacting with chromatin remodeler ATRX. Here we show that TERRA modulates ATRX occupancy on repetitive sequences and over genes, and maintains DNA G-quadruplex structures at TERRA target and non-target sites in mouse embryonic stem cells. TERRA prevents ATRX from binding to subtelomeric regions and represses H3K9me3 formation. G4 ChIP-seq reveals that G4 abundance decreases at accessible chromatin regions, particularly at transcription start sites (TSS) after TERRA depletion; such G4 reduction at TSS is associated with elevated ATRX occupancy and differentially expressed genes. Loss of ATRX alleviates the effect of gene repression caused by TERRA depletion. Immunostaining analyses demonstrate that knockdown of TERRA diminishes DNA G4 signals, whereas silencing ATRX elevates G4 formation. Our results uncover an epigenetic regulation by TERRA that sequesters ATRX and preserves DNA G4 structures.
2022-11-09 | GSE194038 | GEO