Telomere dysfucntion activates YAP1 to drive tissue inflammation [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE144200 | GEO | 2020/02/29
REPOSITORIES: GEO
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Project description:Inflammatory bowel disease (IBD) is a challenging condition with limited therapeutic options. Inflammasome activation is integral to IBD pathogenesis, although the molecular instigators of its activation remain obscure. Here, we establish that telomere dysfunction activates the Yap1 transcriptional co-activator through pATM/c-Abl, which up-regulates expression of microbial receptors Nlrc4 and Nlrc5 and the cytokine pre-IL-18. Microbial engagement of these cytosolic receptors leads to production of mature IL-18, recruiting T cells and other immunocytes which secrete IFN-gamma to drive classical IBD pathology. Genotoxic stress per se (ionizing radiation) can also drive inflammasome activation. Alleviation of IBD pathology can be achieved via telomerase reactivation in intestinal epithelium, antibiotic treatment or pharmacological inhibition of Yap1 - reducing Nlrc4/5 expression as well as IL-18 and IFN-gamma production. Thus, telomere dysfunction-induced inflammasome activation identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating potential novel therapeutic strategies for prevention and disease management.
2020-01-01 | GSE108902 | GEO
Project description:Telomere dysfunction activates YAP1 to drive tissue inflammation
| PRJNA429050 | ENA
Project description:Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/ precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway.
2021-10-30 | GSE182424 | GEO
Project description:Telomere dysfucntion activates YAP1 to drive tissue inflammation [ChIP-seq]
| PRJNA603053 | ENA
Project description: Not available
| S-EPMC7505960 | biostudies-literature
Project description:We examined differential expression of genes within 10MBs of telomeres in myoblasts with long or short telomeres We offer telomere looping with telomere length as a partial mechanistic explanation for the changes gene expression that is observed. Compare expression of genes within 10MB of the telomere in normal myoblasts with long (15 kb) and short (6 kb) telomeres.
2014-07-17 | E-GEOD-48973 | biostudies-arrayexpress
Project description:We examined differential expression of genes within 10MBs of telomeres in myoblasts with long or short telomeres We offer telomere looping with telomere length as a partial mechanistic explanation for the changes gene expression that is observed.
2014-07-17 | GSE48973 | 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:Limitless reproductive potential is one of the hallmarks of cancer cells1. This ability is accomplished by maintaining telomeres, which erosion otherwise causes cellular senescence or death. Human cancer cells often maintain shorter telomeres than do cells in surrounding normal tissues2-5. While most cancer cells activate telomerase, which can elongate telomeres6, it remains elusive why cancer cells keep telomeres short. Here we show that forced elongation of telomeres in cancer cells promotes their differentiation in a tumor microenvironment in vivo. We elongated telomeres of human prostate cancer PC-3 cells, which possess short telomeres7, by enhancing their telomerase activity. The resulting cells with long telomeres retain an ability to form tumors in a mouse xenograft model. Strikingly, these tumors exhibit many duct-like structures and reduced N-cadherin expression, reminiscent of well-differentiated adenocarcinoma. These phenotypic changes are caused by telomere elongation per se but not enhanced telomerase activity. Gene expression profiling revealed that telomere elongation correlates with inhibition of cell-cycle processes. Together, our results suggest a functional contribution of short telomeres to tumor malignancy by regulating cancer cell differentiation. Two samples are telomere-elongated cells, both in the presence and absence of the exogenous hTERT. The other two samples are control cell lines.
2013-05-31 | E-GEOD-36649 | biostudies-arrayexpress
Project description:Telomere erosion causes cell mortality, suggesting that longer telomeres allow greater number of cell division. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than the surrounding normal tissues. Recently, we have shown that telomere elongation in cancer cells represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by long telomeres. Here we report that telomeric repeat-containing RNA (TERRA) induces genome-wide alteration of gene expression in telomere-elongated cancer cells in vivo. Using three different cell lines, we found that telomere elongation upregulates TERRA and downregulates innate immune genes in vivo xenograft tumors. Most of the suppressed genes belonged to innate immune system categories and were upregulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy through suppression of innate immune genes. Four samples are telomere-elongated cells (PC3/LhTERTL, PC3/LhTERTL/cre, HBC4/hTERT and MKN74/hTERT), and the other four samples are control cell lines.
2015-02-05 | E-GEOD-56177 | biostudies-arrayexpress