Telomerase-expressing distributed hepatocyte stem cells repopulate the liver during homeostasis and injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104415 | GEO | 2018/01/18
REPOSITORIES: GEO
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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
Project description:Telomerase reverse transcriptase (TERT) and the noncoding telomerase RNA (TR) subunit constitute the core of telomerase. We now report that the putative F-box protein Pof8 is also a constitutive component of active telomerase in fission yeast. Pof8 functions in a hierarchical assembly pathway by promoting the binding of the Lsm2-8 complex to telomerase RNA, which in turn promotes binding of the catalytic subunit. Loss of Pof8 reduces TER1 stability, causes a severe assembly defect and results in critically short telomeres. Structure profile searches identified similarities between Pof8 and telomerase subunits from ciliated protozoa, making Pof8 next to TERT the most widely conserved telomerase subunits identified to date.
2018-02-09 | GSE104672 | GEO
Project description:Ribonucleoprotein enzymes require specific and dynamic conformations of their RNA constituents for regulated catalysis. Telomerase RNA components (TRs) rely on two conserved domains, a pseudoknot/template sequence and a three-way junction (CR4/5), each of which binds the telomerase reverse transcriptase protein (TERT). Vertebrate TRs evolved a third element, the H/ACA domain, involved in assembly and trafficking of telomerase through binding telomerase cofactors, dyskerin and TCAB1, respectively. Here, we show that telomerase unexpectedly requires TCAB1 for enzyme catalysis and for shaping the conformation of the TR CR4/5 domain. Human and mouse cells lacking TCAB1 exhibit a marked reduction in telomerase activity, but show no defect in enzyme assembly. Instead, loss of TCAB1 causes specific unfolding of critical RNA helices in TR CR4/5 required for catalysis, and impairs TR-TERT association. CR4/5 mutations derived from patients with the telomere disorder dyskeratosis congenita phenocopy the loss of enzyme activity and disruption of TERT binding observed with TCAB1 deletion. These findings show that the H/ACA element acquired by telomerase during vertebrate evolution serves an unanticipated role in controlling folding of the essential TR CR4/5 domain, facilitating optimal TERT engagement and enabling telomerase catalysis through the action of TCAB1 protein tethered at the H/ACA domain.
2018-06-24 | GSE97486 | GEO
Project description:Telomerase-expressing distributed hepatocyte stem cells repopulate the liver during homeostasis and injury
| PRJNA412544 | ENA
Project description:Telomeres are the nucleoprotein structures found at the ends of eukaryotic chromosomes. Conventional DNA polymerases are unable to fully replicate the telomeric end of the chromosome, which leads to a progressive loss of DNA after every cell division. This problem is solved by the ribonucleoprotein enzyme, telomerase. Proper maintenance of the telomeric end is critical for maintaining genome integrity in eukaryotes. The telomerase enzyme has two essential components: the telomerase RNA (TR), which provides the template required for telomeric DNA synthesis; and the catalytic protein telomerase reverse transcriptase (TERT) that catalyzes the extension of the telomeric DNA ends using the TR as a template. The action of telomerase prevents the progressive shortening of the telomeres after every cell division. The TR can form a large structural scaffold upon which many accessory proteins can bind to and form the complete telomerase holoenzyme in vivo. These accessory proteins are required for telomerase activity and regulation inside of cells. The interacting partners of the TERT protein have been extensively characterized in yeast, human, and Tetrahymena systems. These interactors have not been extensively studied in lower eukaryotes including clinically relevant human parasites, such as Trypanosoma brucei (T. brucei). To this end, we performed co-immunoprecipitation coupled to LC-MS/MS of TbTERT-FLAG-HA-HA from T. brucei cells using an anti-TbTERT antibody and protein G magnetic beads. An isotype matched IgG control was performed in tandem. Comparisons of enriched proteins in the IP vs. IgG control revealed previously known and novel interactors of TbTERT. These findings suggest potential mechanistic differences in telomere maintenance in T. brucei compared to higher eukaryotes.
2023-03-08 | PXD038235 | Pride
Project description:Reactivation of the telomerase reverse transcriptase subunit, TERT, is linked to tumourigenesis due to well-documented telomere-dependent and independent functions. The aim of this study was to investigate the effect of the telomerase inhibitor, MST-312, on TERT functions, focusing in particular, on its effects on MYC stabilty and MYC-regulated pathways, in order to assess its potential as a therapeutic agent. We demonstrate that MST-312 reduces MYC levels in cancer cells, leading to reduced MYC levels on chromatin, and subsequently affecting the MYC-regulated transcriptional program. As a result, MST-312 treatment increases the survival of lymphoma-bearing mice. Mechanistically, MST-312 affects the conformation of TERT, leading to TERT/Terc dissociation, and the subsequent loss of both its telomere-dependent and independent functions. Based on the presented data, we conclude that MST-312 treatment is a promising therapeutic strategy, in particular, in MYC-driven tumorus.
2020-01-01 | GSE77014 | GEO
Project description:Reactivation of the telomerase reverse transcriptase subunit, TERT, is linked to tumourigenesis due to well-documented telomere-dependent and independent functions. The aim of this study was to investigate the effect of the telomerase inhibitor, MST-312, on TERT functions, focusing in particular, on its effects on MYC stabilty and MYC-regulated pathways, in order to assess its potential as a therapeutic agent. We demonstrate that MST-312 reduces MYC levels in cancer cells, leading to reduced MYC levels on chromatin, and subsequently affecting the MYC-regulated transcriptional program. As a result, MST-312 treatment increases the survival of lymphoma-bearing mice. Mechanistically, MST-312 affects the conformation of TERT, leading to TERT/Terc dissociation, and the subsequent loss of both its telomere-dependent and independent functions. Based on the presented data, we conclude that MST-312 treatment is a promising therapeutic strategy, in particular, in MYC-driven tumorus.
2020-01-01 | GSE77061 | GEO
Project description:Rationale and Objectives: Cellular therapies are hampered by poor survival and growth of grafts. We recently showed that the survival and repairing capacity of transplanted adult cells may be improved by co-expression of the anti-senescence telomerase reverse transcriptase (TERT) and anti-apoptotic myocardin (MYOCD). The current study aimed at testing whether forced co-expression of TERT and MYOCD improves post-infarct revascularization and tissue repair by adipose tissue-derived mesenchymal stromal cells (AT-MSCs). Methods: We transplanted AT-MSCs engineered to overexpress MYOCD and TERT in a murine model of acute myocardial infarction (AMI). We analyzed the immunoregulatory properties of AT-MSCs on post-AMI. We characterized in vitro and in vivo paracrine effects of AT-MSCs and their interactions with murine cardiospheres (CSps), all as parts of their reparative repertoire. Results: When transplanted into infarcted hearts of C57BL/6 mice, “rejuvenated” AT-MSCs overexpressing TERT and MYOCD (rAT-MSCs) decreased fibrosis and the intrafibrotic CD3 and B220 lymphocyte infiltration, and increased arteriolar density as well as ejection fraction compared with saline or mock-transduced AT-MSCs. These effects were accompanied by increased numbers of Ki-67+ and CD117+ cells, and the expression of cardiac actin and β-myosin heavy chain within the infarcted hearts. Both rAT-MSCs and their conditioned medium (CM) stimulated intracellular Ca2+ flux in CSps. CSp-derived cells had increased survival when preconditioned with CM or exosome-enriched fraction (Exo+) from rAT-MSCs and then exposed to simulated ischemia/reperfusion. Proteomic analysis of rAT-MSCs-Exo+ predicted the activation of vascular development and the inhibition of immune cell trafficking. Elevated concentration of miR-320a, miR-150-5p and miR-126-3p associated with regulation of apoptosis and vasculogenesis was confirmed in rAT-MSCs-Exo+. Conclusions: rAT-MSCs promote vasculogenesis and cell survival and reduce post-AMI inflammatory responses in a murine model of AMI. An integrated experimental and computational analysis revealed that Exo+ is the active component of the paracrine secretion by rAT-MSCs, with pro-angiogenic and pro-survival activities.
2020-12-02 | PXD017413 | Pride
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
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