The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance

Teichroeb, Jonathan H.; Kim, Joohwan; Betts, Dean H.

doi:10.1080/15476286.2015.1134413

Cited by 33 publications

(23 citation statements)

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“…AS and APA are considered to be the major mechanisms of generating transcriptome complexity and thus the expansion of proteome diversity of higher organisms (Lu et al 2010;Mudge et al 2011;Frankish et al 2012). These post-transcriptional mechanisms have been reported to play critical roles in differentiation (Wang et al 2009;Martinez and Lynch 2013;Raj and Blencowe 2015;Teichroeb et al 2016), speciation (McGuire et al 2008;Mudge et al 2011), and multiple human diseases such as cancer (Ladomery 2013;Liu and Cheng 2013;Chen and Weiss 2014), diabetes (Eizirik et al 2012;Tang et al 2015), and neurological disorders (Yang et al 1998;D'Souza et al 1999;Kanadia et al 2003;Ladd 2013;Lee et al 2016) and therefore may play a fundamental role in the establishment of organismal complexity (Black 2003;Mudge et al 2011;La Cognata et al 2014). The genomewide analysis of AS has been done primarily using exon microarrays first and, more recently, short-read RNA-seq.…”

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confidence: 99%

SQANTI: extensive characterization of long-read transcript sequences for quality control in full-length transcriptome identification and quantification

et al. 2018

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High-throughput sequencing of full-length transcripts using long reads has paved the way for the discovery of thousands of novel transcripts, even in well-annotated mammalian species. The advances in sequencing technology have created a need for studies and tools that can characterize these novel variants. Here, we present SQANTI, an automated pipeline for the classification of long-read transcripts that can assess the quality of data and the preprocessing pipeline using 47 unique descriptors. We apply SQANTI to a neuronal mouse transcriptome using Pacific Biosciences (PacBio) long reads and illustrate how the tool is effective in characterizing and describing the composition of the full-length transcriptome. We perform extensive evaluation of ToFU PacBio transcripts by PCR to reveal that an important number of the novel transcripts are technical artifacts of the sequencing approach and that SQANTI quality descriptors can be used to engineer a filtering strategy to remove them. Most novel transcripts in this curated transcriptome are novel combinations of existing splice sites, resulting more frequently in novel ORFs than novel UTRs, and are enriched in both general metabolic and neural-specific functions. We show that these new transcripts have a major impact in the correct quantification of transcript levels by state-of-the-art short-read-based quantification algorithms. By comparing our iso-transcriptome with public proteomics databases, we find that alternative isoforms are elusive to proteogenomics detection. SQANTI allows the user to maximize the analytical outcome of long-read technologies by providing the tools to deliver quality-evaluated and curated full-length transcriptomes.

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confidence: 99%

SQANTI: extensive characterization of long-read transcript sequences for quality control in full-length transcriptome identification and quantification

et al. 2018

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“…Telomere maintenance is critical for the unlimited self-renewal, stemness, and genomic homeostasis of PSCs [76]. Telomere length represents another important criterion for defining stem cell pluripotency, and modulation of telomere length may present great potential in the application of PSCs in regenerative medicine [77].…”

Section: Alt In Pluripotent Stem Cells (Pscs)mentioning

confidence: 99%

Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells

Zhao

Feng

Liu

2019

Genes

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A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine.

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“…In other cases, the upregulation of telomerase is also associated with, and a biomarker of, some cancers, because it allows the unchecked proliferation of immortalised tumour cells [6,8]. Telomerase also has many non-canonical roles, in which telomere maintenance, or even telomerase activity, is not required [9,10]. For example, telomerase is known to have non-canonical roles in neuronal differentiation [11], RNA silencing [12], enhanced mitochondrial function [13] and various cancers [9,14].…”

Section: Introductionmentioning

confidence: 99%

A telomerase with novel non-canonical roles: TERT controls cellular aggregation and tissue size inDictyostelium

Nassir

Hyde

Baskar

2019

Preprint

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11Telomerase, particularly its main subunit, the reverse transcriptase, TERT, prevents DNA 12 erosion during eukaryotic chromosomal replication, but also has poorly understood non-13 canonical functions. Here, in the model social amoeba Dictyostelium discoideum, we show 14 that the protein encoded by tert has telomerase-like motifs and regulates, non-canonically, 15 important developmental processes. Expression levels of wild-type (WT) tert were biphasic, 16 peaking at 8 and 12 h post-starvation, aligning with developmental events, such as the 17 initiation of streaming (~7 h) and mound formation (~10 h). In tert KO mutants, however, 18 aggregation was delayed until 16 h. Large, irregular streams formed, then broke up, leading 19 to small mounds. The mound-size defect was not induced when a KO mutant of countin (a 20 master size-regulating gene) was treated with TERT inhibitors but anti-countin antibodies did 21 rescue size in the tert KO. Further, conditioned medium from countin mutants failed to 22 rescue size in the tert KO, but the converse experiment worked. These and additional 23 the migration of cells that form each fruiting body is delayed and irregular. These results are 48 significant because they show, for the first time, that a telomerase can influence cell 49 migration and tissue size regulation, two processes involved in a wide range of cancers. 50 51 Introduction 52 Each time a chromosome replicates, it loses some DNA from each of its ends. This is not 53 necessarily problematic, because the chromosome is initially capped at each end by a 54 sacrificial strand of non-coding DNA, a telomere [1][2][3]. Further instances of replication, 55 however, can expose the coding DNA, unless the cell can keep repairing the shortened 56 telomeres, by the action of the enzyme complex, telomerase. Accordingly, telomerase, whose 57 main subunits comprise a reverse transcriptase (TERT), and the telomerase RNA component 58 (TERC) [4], has much significance in the biology and pathology of multicellular organisms. 59As somatic tissues age, for example, telomerase is downregulated, and the resulting telomeric 60 dysfunction can lead to chromosomal instability and various pathologies, including disrupted 61 pregnancies and cancer [5][6][7]. In other cases, the upregulation of telomerase is also associated 62 with, and a biomarker of, some cancers, because it allows the unchecked proliferation of 63 immortalised tumour cells [6, 8]. Telomerase also has many non-canonical roles, in which 64 telomere maintenance, or even telomerase activity, is not required [9, 10]. For example, 65 telomerase is known to have non-canonical roles in neuronal differentiation [11], RNA 66 silencing [12], enhanced mitochondrial function [13] and various cancers [9, 14]. 67Our understanding of telomeres and telomerase began, and has continued to develop, through 68 the study of model organisms such as Drosophila, Zea mays, Tetrahymena, yeast and mice 69 [2, 3,[15][16][17][18][19]]. One model system in which the possible roles of telomerase hav...

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The role of telomeres and telomerase reverse transcriptase isoforms in pluripotency induction and maintenance

Cited by 33 publications

References 171 publications

SQANTI: extensive characterization of long-read transcript sequences for quality control in full-length transcriptome identification and quantification

SQANTI: extensive characterization of long-read transcript sequences for quality control in full-length transcriptome identification and quantification

Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells

A telomerase with novel non-canonical roles: TERT controls cellular aggregation and tissue size inDictyostelium

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