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Telomere dysfucntion activates YAP1 to drive tissue inflammation [ChIP-seq]

ABSTRACT: Telomere dysfucntion activates YAP1 to drive tissue inflammation [ChIP-seq]

PROVIDER: PRJNA603053 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10960951.fastq.gz	Fastqsanger.gz
	SRR10960952.fastq.gz	Fastqsanger.gz
	SRR10960953.fastq.gz	Fastqsanger.gz
	SRR10960954.fastq.gz	Fastqsanger.gz
	SRR10960955.fastq.gz	Fastqsanger.gz

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Telomere dysfunction activates YAP1 to drive tissue inflammation

Project description:Telomere dysfunction activates YAP1 to drive tissue inflammation

| PRJNA429050 | ENA

Telomere dysfunction activates YAP1 to drive tissue inflammation

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

Telomere dysfucntion activates YAP1 to drive tissue inflammation [ChIP-seq]

Project description:Germline telomere maintenance defects provoke inflammatory disease via activated ATM/YAP1/IL-18 signaling in epithelial cells, providing novel therapies for inflammatory conditions associated with short telomeres.

2020-02-29 | GSE144200 | GEO

Telomere dysfunction activates YAP1 to drive tissue inflammation.

Project description:Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.

| S-EPMC7505960 | biostudies-literature

Telomere dysfunction instigates inflammation in inflammatory bowel disease

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

YAP1 fusion proteins drive forebrain ependymoma tumorigenesis via the interaction with TEAD transcription factors

Project description:A mouse model has been generated resembling human YAP1 fusion-positive supratentorial ependymoma. We show that the YAP1-MAMLD1 fusion, which is the most recurrent fusion in this distinct type of ependymomas, is able to drive malignant transformation in mice. The resulting brain tumors resemble histo-molecular characteristics of their human counterparts.

2019-08-06 | GSE110625 | GEO

Telomere dysfunction instigates inflammation in inflammatory bowel disease

Project description:Telomere dysfunction instigates inflammation in inflammatory bowel disease

| PRJNA756242 | ENA

ILF3 safeguards telomere from aberrant homologous recombination as a telomeric R-loop reader

Project description:Here we found that ILF3 prefers to bind telomere R-loops and protects telomere from aberrant homologous recombination. ILF3 knockout induces TERRA aggregation onto telomere and activates telomere DNA damage response (DDR). Furthermore, ILF3 deficiency disrupts telomere homeostasis and induces abnormal ALT-mediated telomere lengthening

2022-03-04 | PXD032093 |

Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice [human]

Project description:We analyzed the expression profiles of human and mouse meningiomas (driven by NF2 loss, YAP1-MAML2, TRAF7/KLF4/SMO1/AKT1, or constitutively active non-fusion YAP1). We found that YAP1-MAML2 meningiomas resemble NF2mutant tumors and constitutively exert de-regulated YAP1 activity that is dependent on the interaction with TEADs.

2022-09-02 | GSE199549 | GEO

Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice [mouse]

2022-09-02 | GSE199562 | GEO