Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Endogenous p53 Inhibitor TIRR Dissociates Systemic Metabolic Health from Oncogenic Activity - RNAseq data

ABSTRACT: It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR’s oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE210900 | GEO | 2024/06/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

NEAT1 Modulates the TIRR/53BP1 Complex to Maintain Genome Integrity

Project description:Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying NEAT1_1, the short isoform of the long noncoding RNA NEAT1, as the primary RNA partner. The high affinity of TIRR for NEAT1_1 is due to prevalent G-rich motifs in NEAT1_1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1's function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1’s function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting NEAT1_1 production. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.

2024-09-04 | GSE276206 | GEO

Double strand break repair protein TIRR regulates RNA metabolism in response to DNA damage and cell stress [RIP-seq]

Project description:Tudor interacting repair regulator (TIRR) is a well-studied p53 binding protein 1 (53BP1) interactor in response to DNA double strand breaks (DSBs). TIRR is also an RNA binding protein, however its role in RNA regulation in response to cellular insults is not understood. Here we show that TIRR binds to specific group of mRNAs in response to DNA damage. TIRR bound transcripts encode for transcription factors and RNA polymerase II (RNAPII) transcription regulators. Furthermore, TIRR modulates the formation of RNA processing bodies (P bodies/PBs), in response to DSBs. TIRR also regulates the formation of the closely related but distinct compartments known as stress granules (SGs) in response to cell stress. Furthermore, TIRR dissociates from 53BP1 in response to sodium arsenite treatment independently of Ataxia Telangiectasia Mutated Protein (ATM) signalling. Finally, TIRR interacts with the nuclear export protein Exportin-1 (XPO1) upon DNA damage. TIRR bound RNA co-localises with PB and SGs and TIRR depletion leads to nuclear RNA retention. This work reveals that TIRR orchestrates mRNA nuclear export, metabolism and storage in PBs/SGs. Hence TIRR regulates RNA mediated DNA damage and cell stress responses independently of its canonical 53BP1 binding role.

2024-07-18 | GSE227684 | GEO

Double strand break repair protein TIRR regulates RNA metabolism in response to DNA damage and cell stress [RNA-Seq]

2024-07-18 | GSE248032 | GEO

Endogenous p53 Inhibitor TIRR Dissociates Systemic Metabolic Health from Oncogenic Activity - RNAseq data

Project description:Endogenous p53 Inhibitor TIRR Dissociates Systemic Metabolic Health from Oncogenic Activity - RNAseq data

| PRJNA868216 | ENA

Adipocyte p53 coordinates the adipose tissue immune cell landscape upon intermittent fasting

Project description:In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, its fasting regimen-dependent regulation is unknown. Here, we show that cyclic intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, we provide evidence that this increase in LAM abundance is almost entirely dependent on p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation in AT during IF and increases the catabolic state of adipocytes, ameliorates metabolic flexibility, and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to long-term efficacy of a fasting-mimicking diet and that the expression of LAM markers and p53 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signaling in adipocytes dictates LAM accumulation in AT under IF and that adipocyte p53 modulates fasting effectiveness in mice and humans.

2024-01-16 | PXD041351 | Pride

Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity [RNA-Seq]

Project description:Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.

2024-07-16 | GSE235302 | GEO

Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity [scRNA-Seq]

2024-07-16 | GSE234884 | GEO

Gene Expression Signature in Adipose Tissue of Acromegaly Patients

Project description:OBJECTIVE: Acromegaly is a rare endocrine disorder with excess growth hormone (GH) production. This disorder has important metabolic effects in insulin resistance and lipolysis. The objective of this study was to explore transcriptional changes induced by GH in adipose tissue. METHODS: The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex-vivo for lipolysis and ceramide levels. Adipose tissue was analyzed by RNA sequencing (RNA-seq). RESULTS: There was evidence of reduced insulin sensitivity based on the increase in fasting glucose, insulin and HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3) as well as several novel transcriptional changes, some of which may be important for GH signal regulation (PTPN3 and PTPN4) and the effect of GH on growth and proliferation. Several transcripts could potentially be important in GH-induced metabolic changes. Specifically, induction of LPL, ABHD5, and ACVR1C could contribute to enhanced lipolysis and may explain the suggestive enhancement of adipose tissue lipolysis in acromegaly patients as reflected by glycerol release from the explants of the two groups of patients (p=0.09). Higher expression of SCD and TCF7L2 could contribute to insulin resistance. Expression of HSD11B1 was reduced and GR was increased, predicting modified glucocorticoid activity in acromegaly. CONCLUSIONS: We identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly. DESIGN: Patients with acromegaly (n=9) or non-functioning pituitary adenoma (n=11) were prospectively observed from March 2011 to June 2012. Sequencing was performed on RNA from 7 acromegaly patients and 11 controls.

2015-05-01 | E-GEOD-57803 | biostudies-arrayexpress

MBOAT7-Driven Lysophosphatidylinositol Acylation in Adipocytes Contributes to Systemic Glucose Homeostasis

Project description:We previously demonstrated that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7, the gene encoding Membrane Bound O-Acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated floxed Mboat7 mice and created hepatocyte- and adipocyte-specific knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. After chow and high fat diet feeding (60% kCal fat), mice were subjected to metabolic phenotyping and tissues to molecular workup and analysis. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ~100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

2023-05-10 | PXD039894 | Pride

System level analysis of insulin action revels insight into whole body metabolism and insulin action in muscle and adipose tissue

Project description:Muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance specifically in these tissues, we leveraged the metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin resistance. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin action. The A/J strain in particular exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.

2022-02-24 | PXD029680 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data