An intact putative mouse telomerase essential N‐terminal domain is necessary for proper telomere maintenance

Rousseau, Philippe; Khondaker, Shanjadia; Zhu, Shusen; Lauzon, Catherine; Mai, Sabine; Autexier, Chantal

doi:10.1111/boc.201500089

Cited by 5 publications

(3 citation statements)

References 74 publications

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“…Exclusion of hTERT exon-2 serves to completely repress telomerase activity in somatic cells and enforces the tumor suppressor function of telomere shortening. This is supported by the identification of TERT alternative splice variants in additional species, as evolutionarily distant as Planarians (26, 43,44). Our study also implicates SON in the regulation of this key alternative splicing switch and we link SON mutations with telomere shortening in a DC patient.…”

supporting

confidence: 71%

Alternative splicing is a developmental switch for hTERT expression

Penev¹,

Bazley²,

Shen

et al. 2020

Preprint

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2 Penev et al.,High telomerase activity is restricted to the blastocyst stage of embryonic development when telomere length is reset, and is characteristic of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, the pathways involved in telomerase regulation as a function of pluripotency remain unknown. To explore hTERT transcriptional control, we compare genome-wide interactions (4C-seq) and chromatin accessibility (ATAC-seq) between human ESCs and epithelial cells and identify several putative hTERT cis-regulatory elements. CRISPR/Cas9-mediated deletion of candidate elements in ESCs reduces the levels of hTERT mRNA but does not abolish telomerase expression, thus implicating post-transcriptional processes in telomerase regulation. In agreement with this hypothesis, we find an hTERT splice variant lacking exon-2 and prone to degradation, to be enriched in differentiated cells but absent from ESCs. In addition, we show that forced retention of exon-2 prevents telomerase silencing during differentiation.Lastly, we highlight a role for the splicing co-factor SON in hTERT exon-2 inclusion and identify a SON mutation in a Dyskeratosis congenita patient with short telomeres and decreased telomerase activity. Altogether, our data uncover a novel alternative splice switch that is critical for telomerase activity during development.Telomerase counteracts telomere erosion and promotes cellular immortality. This specialized ribonucleoprotein complex is minimally composed of a reverse-transcriptase protein subunit (TERT) and an integral telomerase RNA component (TR). While the expression of telomerase RNA is ubiquitous (1, 2), TERT levels are tightly regulated (3). Human TERT (hTERT) is turned on during the blastocyst stage of embryonic development when telomere length is reestablished (4), and subsequently downregulated in most somatic cells (4,5). Similarly, hTERT becomes activated during the process of nuclear reprogramming (6) and is essential for telomere maintenance in pluripotent cells (7). Upregulation of telomerase occurs in approximately 90% of cancers, allowing tumor cells to escape crisis and proliferate indefinitely (5,8). Somatic mutations in the hTERT promoter have been reported in a subset of cancers and shown to increase telomerase activity by creating a binding site for ETS family transcription factors (9-11). To date, the underlying mechanism that activates hTERT during development and its subsequent silencing in somatic tissues remains unknown.The core hTERT promoter contains numerous binding sites for pluripotency and growthrelated transcription factors, including Myc, Klf4, and Sp1, but expression of these different factors 3 Penev et al., is not sufficient for hTERT accumulation and telomerase activation in somatic cells (12). We therefore sought to identify cis-regulatory elements (REs) that could account for the difference in hTERT mRNA levels between pluripotent and somatic cells ( Figure S1A). Active REs are known to directly contact the promoters they regulate and h...

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supporting

confidence: 71%

Alternative splicing is a developmental switch for hTERT expression

Penev¹,

Bazley²,

Shen

et al. 2020

Preprint

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“…This would indicate that the TERT molecule present in the Older Women Group is not strictly the same as the one present in the Older Men Group. In fact, it is known that TERT has different isoforms with different activities (Rousseau et al, 2016 ). In any case, the action of IGF1 is important, because in contrast with LIF, IGF1 leads to proliferation and lineage commitment of cell precursors of astrocytes, oligodendroglia and neurons (Pati et al, 2014 ), while the shortening of telomeres due to lower TERT activity is involved in the phenomenon of replicative senescence (Wei et al, 2015 ; Pérez-Martín et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Sexual Dimorphism and Aging in the Human Hyppocampus: Identification, Validation, and Impact of Differentially Expressed Genes by Factorial Microarray and Network Analysis

Guebel¹,

Torres

2016

Front. Aging Neurosci.

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Motivation: In the brain of elderly-healthy individuals, the effects of sexual dimorphism and those due to normal aging appear overlapped. Discrimination of these two dimensions would powerfully contribute to a better understanding of the etiology of some neurodegenerative diseases, such as “sporadic” Alzheimer.Methods: Following a system biology approach, top-down and bottom-up strategies were combined. First, public transcriptome data corresponding to the transition from adulthood to the aging stage in normal, human hippocampus were analyzed through an optimized microarray post-processing (Q-GDEMAR method) together with a proper experimental design (full factorial analysis). Second, the identified genes were placed in context by building compatible networks. The subsequent ontology analyses carried out on these networks clarify the main functionalities involved.Results: Noticeably we could identify large sets of genes according to three groups: those that exclusively depend on the sex, those that exclusively depend on the age, and those that depend on the particular combinations of sex and age (interaction). The genes identified were validated against three independent sources (a proteomic study of aging, a senescence database, and a mitochondrial genetic database). We arrived to several new inferences about the biological functions compromised during aging in two ways: by taking into account the sex-independent effects of aging, and considering the interaction between age and sex where pertinent. In particular, we discuss the impact of our findings on the functions of mitochondria, autophagy, mitophagia, and microRNAs.Conclusions: The evidence obtained herein supports the occurrence of significant neurobiological differences in the hippocampus, not only between adult and elderly individuals, but between old-healthy women and old-healthy men. Hence, to obtain realistic results in further analysis of the transition from the normal aging to incipient Alzheimer, the features derived from the sexual dimorphism in hippocampus should be explicitly considered.

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“…Transcript variants missing segments of hTERT exon 2 were previously reported in murine and avian models, but their function remains unknown (Hrdlickova ´et al, 2012;Rousseau et al, 2016). Similar TERT alternative splice variants were also identified in species as phylogenetically distant as Planarians (Tan et al, 2012) that express robust telomerase activity at the site of blastema formation and facilitate rapid tissue neogenesis.…”

Section: Llmentioning

confidence: 81%