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TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I

ABSTRACT: Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observed that expression of telomerase reverse transcriptase (TERT) is closely associated with immune-suppressive signatures. We demonstrated that TERT can activate a subclass of endogenous retroviruses (ERVs) to form double-stranded RNAs (dsRNAs), which were sensed by the RIG-1/MDA5-MAVS signalling pathway and triggered interferon signalling in cancer cells. Furthermore, we showed that TERT-induced ERVs/interferon signalling stimulated the expression of chemokines, including CXCL10, which induced suppressed T cell infiltration with increased percentage of CD4+ and FOXP3+ cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERVs/interferon signalling contributes to immune suppression in tumours.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169711 | GEO | 2022/02/22

REPOSITORIES: GEO

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TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment III

Project description:Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observed that expression of telomerase reverse transcriptase (TERT) is closely associated with immune-suppressive signatures. We demonstrated that TERT can activate a subclass of endogenous retroviruses (ERVs) to form double-stranded RNAs (dsRNAs), which were sensed by the RIG-1/MDA5-MAVS signalling pathway and triggered interferon signalling in cancer cells. Furthermore, we showed that TERT-induced ERVs/interferon signalling stimulated the expression of chemokines, including CXCL10, which induced suppressed T cell infiltration with increased percentage of CD4+ and FOXP3+ cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERVs/interferon signalling contributes to immune suppression in tumours.

2022-02-22 | GSE169714 | GEO

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

2022-02-22 | GSE169713 | GEO

Evolutionarily conserved role of Telomerase reverse transcriptase (TERT) in programming the microenvironment via regulation of cGAS/STING pathway

Project description:Telomerase holoenzyme plays a critical role in maintaining telomere length, and thus in regulating inflammation caused by telomeric DNA damage. However, beyond its role in telomere maintenance, the molecular function of telomerase in directly regulating inflammation remains unclear. Here, we show that the reverse transcriptase component of telomerase, TERT, has a cell-type-specific role in directly regulating inflammation via the cytoplasmic cGAS-STING nucleic acid-sensing pathway. Analyses of murine and zebrafish models of gut inflammation and human colitis/Crohn’s patients document that this function of TERT is evolutionarily conserved. Using our novel knock-in TERTVAA mouse model where reverse-transcriptase-inactive TERT is driven by its endogenous loci, and molecular, pharmacological and single-cell approaches we identify the myeloid subpopulation, termed T-MAC, wherein TERT enhances STING activation and initiates type-1 interferon responses independent of reverse transcriptase activity or telomere length. We highlight a hitherto unappreciated role of TERT in directly regulating inflammation and provide a therapeutic rationale for targeting TERT beyond cancers.

2024-07-22 | GSE241725 | GEO

Transcription landscape of adipose tissue changes in response to telomerase knockout in mesenchymal progenitors

Project description:We generated mice with telomerase (TERT) gene knock-out (KO) that undergo premature telomere shortening in adipose stromal cells expressing Pdgfra or Pdgfrb. Stromal vascular cells were isolated from inguinal adipose tissue of Pdgfra-Cre; TERT fl/fl mice (Sample name A_SAT), Pdgfrb-Cre; TERT fl/fl mice (Sample name KO_SAT), and of control TERT WT mice (Sample name PBS_SAT).

2020-09-11 | GSE157815 | GEO

Transcription of endogenous retroviruses in pre-senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence

Project description:An important epigenetic switch marks the onset and maintenance of senescence. This allows transcription of the genetic programs that arrest the cell cycle and alter the microenvironment. Transcription of endogenous retroviruses (ERVs) is also a consequence of this epigenetic switch. In this manuscript, we have identified a group of ERVs that are epigenetically silenced in proliferating cells but are upregulated during replicative senescence or during various forms of oncogene-induced senescence, by RAS, Akt, or HDAC4 depletion. In an HDAC4 model of OIS, removal of the repressive histone mark H3K27me3 is the plausible mechanism that allows the transcription of intergenic ERVs during senescence. We have shown that ERVs contribute to the accumulation of dsRNAs in senescence, which can initiate the antiviral response via the IFIH1-MAVS signaling pathway and thus contribute to the maintenance of senescence. This pathway, and MAVS in particular, plays an active role in shaping the microenvironment and maintaining growth arrest, two essential features of the senescence program

2024-02-16 | GSE250348 | GEO

Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

Project description:Genetic lesions that reduce telomerase cause a range of incurable diseases including dyskeratosis congenita (DC) and pulmonary fibrosis (PF), and restoring telomere length in these patients would be curative. Ectopic expression of telomerase reverse transcriptase (TERT) risks cellular immortalization, and how to target telomerase in stem cells throughout the body remains unclear. Here we describe a successful screen for small molecules that augment TERC, the non-coding telomerase RNA component, and thereby specifically elongate telomeres in stem cells. PAPD5 is a non-canonical polymerase that oligo-adenylates and destabilizes TERC. Using a high-throughput screen we identify BCH001, a specific PAPD5 inhibitor that decreases TERC 3′- oligo(A) tailing and increases telomerase activity and telomere length by thousands of nucleotides in DC patient induced pluripotent stem cells (iPSCs). BCH001 does not result in immortalization or telomere elongation in somatic cells which lack TERT, establishing a favorable safety profile. When human hematopoietic stem and progenitor cells (HSPCs) engineered by CRISPR-Cas9 to carry PARN mutations that cause DC and PF are xenotransplanted into immunodeficient mice, oral treatment with PAPD5 inhibitors rescues TERC 3′-end maturation and telomere length. Our data demonstrate telomere restoration in human stem cells in vivo using small molecules.

2020-04-21 | GSE144986 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [TAPR1_KO]

Project description:Telomere erosion in cells with insufficient levels of the telomerase reverse transcriptase, TERT, contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide screen to identify gene deletions that sensitized p53-positive human cells to telomerase inhibition. We uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1, TAPR1, that exhibited a synthetic-sick relationship with TERT loss. A genome-wide screen in TAPR1-disrupted cells also identified TERT as a sensitizing gene deletion. Additional genetic and transcriptome analysis of TAPR1-disrupted cells revealed that TAPR1 tapered p53 activation in response to eroded telomeres, p53 stabilization with nutlin-3a, or DNA damage. Importantly, deletion of TP53 rescued the fitness defect in TAPR1-disrupted cells. These findings identify C16ORF72/TAPR1 as new regulator at the nexus between telomere integrity and p53 regulation.

2021-03-04 | GSE160867 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [RNA-seq]

2021-03-04 | GSE160865 | GEO

A genome-wide screen for essentiality upon telomerase inhibition identifies a novel p53 regulator, C16ORF72/TAPR1 [BIBR_screen]

2021-03-04 | GSE160843 | GEO

Effect of TERT and ATM on Gene Expression Profiles in Human Fibroblasts

Project description:Gene expression profiling was performed by use of serial analysis of gene expression (SAGE) on BJ normal human skin fibroblasts, A-T cells, and BJ and A-T cells transduced with hTERT cDNA and expressing telomerase activity. Keywords = telomere Keywords = telomerase Keywords = TERT Keywords = ataxia telangiectasia mutated Keywords = ATM Keywords = serial analysis of gene expression Keywords = SAGE Keywords = fibroblast Keywords: parallel sample

2004-01-16 | E-GEOD-953 | biostudies-arrayexpress

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