The role of MacroH2A1.2 in cancer (ChIP-Seq)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE168235 | GEO | 2021/05/01
REPOSITORIES: GEO
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Project description:MacroH2A1.2 is a histone variant from H2A family. Expression of macroH2A1.2 is found to be dysregulated in cancer especially lung cancer. However, the role of macroH2A1.2 in lung cancer remains relatively unknown. Our study showed that macroH2A1.2 stabilized FASN expression, increased fatty acid production and hence improved rate of mitochondria respiration. As a result, the cancer cells with higher macroH2A1.2 expression were more metastatic.
2021-05-01 | GSE168236 | GEO
Project description:Obesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exonspliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown. Here we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. Genomic and transcriptomic analyses demonstrated that association of macroH2A1.2 promoter occupancy of key adipogenic genes with their transcripts was gene specific. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects. MacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.
2016-10-01 | GSE85796 | GEO
Project description:The role of MacroH2A1.2 in cancer
| PRJNA706649 | ENA
Project description:The role of MacroH2A1.2 in cancer (ChIP-Seq)
| PRJNA706651 | ENA
Project description:The role of MacroH2A1.2 in cancer (RNA-Seq)
| PRJNA706652 | ENA
Project description:Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for gene regulation, cellular differentiation and accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at genomic regions of recurrent replication stress. Upon aberrant fork stalling within these fragile regions, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT histone chaperone -dependent deposition of macroH2A1.2, a histone H2A variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from replication stress-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of replication stress. Altogether, our findings demonstrate that recurrent DNA damage critically contributes to the chromatin landscape to ensure both the epigenetic and functional integrity of dividing cells.
2017-12-13 | GSE104800 | GEO
Project description:Background: Obesity has become a worldwide concern. Acute respiratory distress syndrome (ARDS) comprises 10.4% of total intensive care unit admissions and is associated with very high mortality. ARDS incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the clinical and pathologic features observed in patients with ARDS. The aim of this study was to determine the impact of high fat diet-induced obesity on the susceptibility to hyperoxic acute lung injury in mice. Methods: Male C57BL/6 mice received 60% fat versus ingredient matched 10% fat diet. Mice were exposed to >95% oxygen to induce lung damage. RNA was isolated from lung homogenates and by comparing RNA sequencing results with mouse Mitocarta, an inventory of genes encoding proteins with mitochondrial localization, we identified fatty acid synthase (FASN), an enzyme catalyzing de novo fatty acid synthesis, as one of the mitochondrial genes significantly changed with diet and with hyperoxia. We generated mice deficient in FASN in alveolar epithelial cells by using a tamoxifen inducible Cre recombinase construct (FASNflox/flox SPC Cre+/-) and subjected them to hyperoxia and high fat diet. Results: Mice receiving 60% fat diet had significantly higher weight, serum cholesterol and fasting glucose. High fat diet mice had significantly reduced survival and increased lung damage, as assessed by BAL protein and LDH, histology and TUNEL staining. By RNA sequencing of lung homogenates we identified FASN as one of the mitochondrial genes significantly reduced in mice receiving 60% compared to 10% fat diet and further reduced with hyperoxia. We confirmed that FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. After 48 hours of hyperoxia FASNflox/flox SPC Cre+/- mice displayed increased levels of BAL protein and LDH and more severe histologic lung injury. FASNflox/flox SPC Cre+/- mice remained more prone to lung injury after hyperoxic exposure even when they received 60% fat diet. Conclusions: These results demonstrate that obesity increases the severity of hyperoxia induced acute lung injury in mice by altering FASN levels in the lung of high fat diet fed rodents. To our knowledge, this is the first study to show that high fat diet leads to altered FASN expression in the lung and that both high fat diet and reduced FASN in alveolar epithelial cells lead to increased lung injury under hyperoxic conditions.
2019-07-25 | GSE123938 | GEO
Project description:USP13 is significantly amplified in over 20% of lung cancer patients and critical for tumor progression. However, the functional role of USP13 in small cell lung cancer (SCLC) remains largely unclear. In this study, we found that the deubiquitinase USP13 is highly expressed in SCLC tumor samples and positively associated with poor prognosis in multiple cohorts. In vitro and in vivo depletion of USP13 inhibited SCLC cancer stem cells (CSCs) properties and tumorigenesis, and this inhibitory effect was rescued by reconstituted expression of wide type (WT) USP13 but not the enzyme-inactive USP13 mutant. Mechanistically, USP13 interacts with fatty acid synthase (FASN) and enhances FASN protein stability. FASN downregulation suppresses USP13-enhanced cell renewal regulator expression, sphere formation ability, and de novo fatty acids biogenesis. Accordingly, we found FASN expression is upregulated in surgical resected SCLC specimens, positively correlated with USP13, and associated with poor prognosis of SCLC patients. More importantly, the small molecule inhibitor of FASN, TVB-2640, significantly inhibits lipogenic phenotype and attenuates self-renewal ability and chemotherapy resistance in SCLC. Thus, our study highlights a critical role of the USP13-FASN-lipogenesis axis in SCLC cancer stemness maintenance and tumor growth, and reveals a potential combination therapy for SCLC patients.
2022-04-06 | PXD032993 |
Project description:Sulfur mustard (HD) is a vesicating agent that targets the eyes, skin, and lungs, producing skin burns, conjunctivitis, and compromised respiratory function. Underlying mechanisms of this damage are a critical area of research for the development of medical countermeasures. This study utilized mRNA analysis to evaluate molecular effects of HD on lung tissue from anesthetized swine inhalationally exposed to HD Anesthetized large swine were exposed for 10 minutes to either air, 60 ug/kg (low), or 100ug/kg (medium) HD vapor. At 12 hours, animals were euthanized, lungs removed and dissected by lobe, and stabilized in RNAlater. Total RNA was isolated and processed for hybridization to Affymetrix Porcine GeneChip.
2016-09-01 | E-GEOD-73088 | biostudies-arrayexpress
Project description:E3 ubiquitin-ligases are important for the cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease.Several mouse models of colitis and associated cancer were used including AOM-DSS, acute colitis, and genetically modified mice deficient for the IL-10 gene, to analyse Hakai expression by immunohistochemistry. Interactome analysis of Hakai was performed and effect on selected protein was determined by plasmid and siRNA transfection, western-blotting, immunoprecipitation, immunofluorescence and ubiquitination assays. Lipid accumulation was assayed by oil red staining. Immunohistochemistry was also performed in inflamed colon biopsies from ulcerative colitis, Crohn's disease and colorectal cancer patients. Our results show that Hakai was downregulated in inflammatory tissues in different mouse models. Fatty Acid Synthase (FASN) protein was identified as a novel Hakai-interacting protein. Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN with Hakai expression was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.
2022-10-25 | PXD029136 | Pride