The NSL complex is required for telomere maintenance and primary piRNA biogenesis from telomeric clusters
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ABSTRACT:
PROVIDER: PRJNA659485 | ENA |
REPOSITORIES: ENA
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Project description:Telomeres cap and protect chromosome ends. Drosophila telomeres consist of repetitive sequences dominated by retrotransposons. Telomeric sequences are transcribed and participate in a negative feedback loop in which they are processed into self-targeting piRNA on the one hand and are serve as the sole source of the transposase responsible for telomere maintenance on the other hand. We show that the tight regulation of the expression of telomeric sequences in the germline is regulated by the NSL complex. As a consequence, both primary biogenesis from telomeric piRNA clusters as well as telomere stability are impaired in cells following NSL complex depletion.
2021-08-26 | GSE156897 | GEO
Project description:Background. Telomeric small RNAs related to PIWI-interacting RNAs (piRNAs) have been described in various eukaryotes; however, their role in germline-specific telomere function remains poorly understood. Using a Drosophila model, we performed an in-depth study of the biogenesis of telomeric piRNAs and their function in telomere homeostasis in the germline. Results To fully characterize telomeric piRNA clusters, we integrated the data obtained from analysis of endogenous telomeric repeats, as well as transgenes inserted into different telomeric and subtelomeric regions. The small RNA-seq data from strains carrying telomeric transgenes demonstrated that all transgenes belong to a class of dual-strand piRNA clusters; however, their capacity to produce piRNAs varies significantly. Rhino, a paralog of heterochromatic protein 1 (HP1) expressed exclusively in the germline, is associated with all telomeric transgenes, but its enrichment correlates with the abundance of transgenic piRNAs. It is likely that this heterogeneity is determined by the sequence peculiarities of telomeric retrotransposons. In contrast to the heterochromatic non-telomeric germline piRNA clusters, piRNA loss leads to a dramatic decrease in HP1, Rhino, and trimethylated histone H3 lysine 9 in telomeric regions. Therefore, the presence of piRNAs is required for the maintenance of telomere chromatin in the germline. Moreover, piRNA loss causes telomere translocation from the nuclear periphery toward the nuclear interior but does not affect telomere end capping. Analysis of the telomere-associated sequences (TASs) chromatin revealed strong tissue specificity. In the germline, TASs are enriched with HP1 and Rhino, in contrast to somatic tissues, where they are repressed by Polycomb group proteins. Conclusions piRNAs play an essential role in the assembly of telomeric chromatin, as well as in nuclear telomere positioning in the germline. Telomeric arrays and TASs belong to a unique type of Rhino-dependent piRNA clusters with transcripts that serve simultaneously as piRNA precursors and as their only targets. Telomeric chromatin is highly sensitive to piRNA loss, implying the existence of a novel developmental checkpoint that depends on telomere integrity in the germline.
2018-07-12 | GSE98981 | GEO
Project description:Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. In addition, recent evidence revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate through the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we developed QTIP-iPOND, which enables purification of the proteins that associate with telomeres during their replication. We identify in addition to the core replisome a large number of proteins that specifically associate with telomere replication forks and validate their importance.
2021-11-03 | PXD018712 | Pride
Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.
2023-10-21 | PXD043084 | Pride
Project description:Telomere is a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes, but in some species or telomerase-defective situations, alternative telomere lengthening (ALT) mechanism is utilized to protect chromosomal ends. Telomere loss can induce telomere recombination by which specific sequences can be recruited into telomeres. However, canonical telomeric repeat-based telomeres have been found in mammals. Here, we show that mammalian telomeres can also be completely reconstituted using a non-telomeric unique sequence. We found that a specific subtelomeric element, named as mouse template for ALT (mTALT), is utilized for repairing telomeric DNA damage and composing new telomeric sequences in mouse embryonic stem cells. We found a high-level of non-coding mTALT transcript despite the heterochromatic nature of mTALT-based telomere. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributed to maintaining telomere stability by regulating telomeric transcriptions. Our findings reveal novel molecular features of potential telomeric sequences which can reconstitute telomeres during cancer formation and evolution.
2020-07-17 | MSV000085772 | MassIVE
Project description:Oxidative stress is a primary cause of cellular senescence and contributes to the pathogenesis of numerous human diseases. Oxidative damage to telomeric DNA is proposed to trigger premature senescence by accelerating telomere shortening. Here we tested this model directly using a precision tool to produce the common base lesion 8-oxoguanine (8oxoG) exclusively at telomeres in human fibroblast and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and delayed mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions which drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.
2022-05-26 | GSE175686 | GEO
Project description:PIWI-interacting (pi) RNAs provide silencing of transposable elements (TE) in the germline. Drosophila telomeres are maintained by transpositions of specialized telomeric retroelements. piRNAs generated from sense and antisense transcripts of telomeric elements provide telomere length control in the germline. Previously, we have found that antisense transcription of the major telomeric retroelement HeT-A is initiated upstream of the HeT-A sense transcription start site. Here, we performed a deletion analysis of the HeT-A promoter and show that common regulatory elements are shared by sense and antisense promoters of HeT-A. Therefore, the HeT-A promoter is a bidirectional promoter capable of processive sense and antisense transcription. Ovarian small RNA data shows that a solo HeT-A promoter within an euchromatic transgene initiates divergent transcription of transgenic reporter genes and subsequent processing of these transcripts into piRNAs. These events lead to the formation of a divergent uni-strand piRNA cluster at solo HeT-A promoters, in contrast to endogenous telomeres that represent strong dual-strand piRNA clusters. Solo HeT-A promoters are not immunoprecipitated with Heterochromatin Protein 1 (HP1) homolog Rhino, a marker of the dual-strand piRNA clusters, but are associated with HP1 itself, which provides piRNA-mediated transcriptional repression of the reporter genes. Unlike endogenous dual-strand piRNA clusters, the solo HeT-A promoter does not produce overlapping transcripts. In a telomeric context, however, bidirectional promoters of tandem HeT-A repeats provide read-through transcription of both genomic strands, followed by Rhi binding. These data indicate that Drosophila telomeres share properties of uni-strand and dual-strand piRNA clusters.
2016-12-07 | GSE78135 | 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:We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukaemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from individuals with the shortest telomeres revealed limited numbers of repeats at the breakpoint, sub-telomeric deletion and microhomology. Array-CGH analysis of individuals displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. Array CGH was undertaken on six individuals (five CLL stage C and one stage A) that displayed evidence of telomere dysfunction, and four (three CLL stage A and one stage B) that displayed longer and apparently stable telomeres.
2010-05-28 | E-GEOD-22016 | biostudies-arrayexpress
Project description:The goal of this experiment is to determine the effect of ATRX depletion on telomeric chromatin compaction. We adapted the ATAC-seq to quantify telomere chromatin accessibility. By scoring the ratio of sequence reads that contained 3 - 12 tandem telomeric repeats over the total number of reads in wild-type and ATRX deplted cells, our analysis revealed that CRISPR/Cas9-mediated ATRX depletion induces a progressive telomere de-compaction.
2019-08-26 | GSE130640 | GEO