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In Vivo Protein Turnover Rates in Varying Oxygen Tensions Nominate MYBBP1A as a Novel Mediator of the Hyperoxia Response

ABSTRACT: Oxygen deprivation and excess are both toxic to mammals. Thus, the body’s ability to adapt to varying oxygen tensions is critical for survival. While the transcriptional response to acute hypoxia has been well-studied, the post-translational effects of hypoxia and hyperoxia have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to changes in oxygen tension, likely due to the direct exposure of alveoli to inhaled oxygen. In particular, several extracellular matrix (ECM) proteins such as collagens and laminins, are stabilized in the lung under both hypoxia and hyperoxia, suggesting their post-translational regulation. Furthermore, we validate our previous finding that complex 1 of the electron transport chain (ETC) is destabilized in hyperoxia, explaining the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a novel transcriptional regulator in hyperoxic lung, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of the effects of oxygen tensions on protein turnover rates and identifies novel tissue-specific mediators of oxygen-dependent responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE234123 | GEO | 2023/12/10

REPOSITORIES: GEO

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In Vivo Protein Turnover Rates in Varying Oxygen Tensions Nominate MYBBP1A as a Novel Mediator of the Hyperoxia Response

Project description:Oxygen deprivation and excess are both toxic to mammals. Thus, the ability to adapt to varying oxygen tensions is critical for survival. While the transcriptional response to acute hypoxia has been well-studied, the post-translational effects of hypoxia and hyperoxia have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to changes in oxygen tension, likely due to the direct exposure of alveoli to inhaled oxygen. In particular, several extracellular matrix (ECM) proteins such as collagens and laminins, are stabilized in the lung under both hypoxia and hyperoxia, suggesting their post-translational regulation. Furthermore, we validate our previous finding that complex 1 of the electron transport chain (ETC) is destabilized in hyperoxia, explaining the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a novel transcriptional regulator in hyperoxic lung, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of the effects of oxygen tensions on protein turnover rates and identifies novel tissue-specific mediators of oxygen-dependent responses.

2023-06-04 | MSV000092095 | MassIVE

Oxygen Toxicity Causes Cyclic Damage by Destabilizing Specific Fe-S Cluster-Containing Protein Complexes

Project description:Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular pathways affected by excess molecular oxygen. We find that hyperoxia destabilizes a specific subset of Fe-S cluster (ISC)-containing proteins, resulting in impaired diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings translate to primary human lung cells and a mouse model of pulmonary oxygen toxicity. We demonstrate that the ETC is the most vulnerable to damage, resulting in decreased mitochondrial oxygen consumption. This leads to further tissue hyperoxia and cyclic damage of the additional ISC-containing pathways. In support of this model, primary ETC dysfunction in the Ndufs4 KO mouse model causes lung tissue hyperoxia and dramatically increases sensitivity to hyperoxia-mediated ISC damage. This work has important implications for hyperoxia pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.

2023-03-18 | GSE224583 | GEO

Oxygen Toxicity Causes Cyclic Damage by Destabilizing Specific Fe-S Cluster-Containing Protein Complexes

2023-02-05 | MSV000091206 | MassIVE

Transcriptome Analysis Reveals Gene Expression Changes in a mouse Model of Hyperoxia-induced acute lung injury

Project description:Oxygen therapy is essential for cure critically patients in ICU, but hyperoxia can cause damage to many organs, including the lungs, leading to Hyperoxia Acute Lung Injury (HALI), a mild type of acute respiratory distress syndrome (ARDS). However, the comprehensive pathogenesis and regulation mechanisms underlying the development of HALI remain unclear. In this study, we conducted a mouse model with hyperoxia treatment and sequenced the gene expression pattern of HALI-mice and relative control (RNA-seq).

2024-04-05 | GSE237260 | GEO

Se Deficiency Exacerbates Hyperoxia-Induced Lung Injury in Newborn C3H/HeN Mice

Project description:Extremely preterm infants are often treated with supraphysiological oxygen which contributes to the development of bronchopulmonary dysplasia (BPD). These same infants exhibit compromised antioxidant capacities due in part to selenium (Se) deficiency. The present study was designed to develop a perinatal Se deficiency mouse model, identify the effects of newborn hyperoxia exposure, and explore alternative pathways affected by Se deficiency (SeD) that would contribute to impaired lung development. Se deficient breeding pairs were generated, once pups were born, they were exposed to room air or 85% O2 for 14 d. Survival, antioxidant and Nrf2-regulated protein expression, and RNA seq analyses were performed. Greater than 40% mortality was observed in Se deficient (SeD), hyperoxia exposed pups. Surviving SeD pups had greater lung growth deficits than Se sufficient (SeS) pups exposed to hyperoxia. Gpx2 and 4 protein and Gpx activity were significantly decreased in SeD pups. Nrf2-regulated proteins, NQO1 and Gclc were increased in the setting of Se deficiency and hyperoxia exposure. RNA seq revealed significant decreases in the Wnt/-catenin and Notch pathways. Se is a biologically relevant modulator of perinatal lung development and antioxidant responses, especially in the context of hyperoxia exposure. RNA seq implicates pathways essential for normal lung development are dysregulated by Se deficiency.

2024-05-01 | GSE255744 | GEO

Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes

Project description:The central nervous system normally functions at O2 levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O2-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O2 tensions compared to the cell culture standard of 20% O2, to investigate their ability to sense and translate this O2 information to transcriptional activity. Variance of ambient O2 tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O2 tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O2 tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O2 tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional ‘programs’ may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity.

2012-09-20 | GSE29296 | GEO

Expression data from 8-10 week old WT mice maintained in room air or exposed to hyperoxia (FiO2>95%) for 48 hrs

Project description:To detect sex-specific differences in gene expression in a model of hyperoxic lung injury in adult C56BL/6J mice. In this dataset, we include the expression data obtained from lungs from 8-10 week old male and female WT C57BL/6J mice exposed to hyperoxia for 48 hours amd room air controls.These data were used to determine differences in transcriptome between male and female mice after hyperoxia exposure 12 total samples were analyzed. We generated the following pairwise comparisons: 5 comparisons (M/F: male/female, A/O: air/oxygen): 1) M_O - M_A,  2) F_O - F_A, 3) M_O - F_O, 4) M_A - F_A, 5) (M_O - M_A) - (F_O - F_A). Genes with an FDR≤5% and a fold-change ≥1.4 were selected.

2014-12-10 | E-GEOD-51039 | biostudies-arrayexpress

In vivo hyperoxia versus normoxia neonatal rat lung MSCs

Project description:Background: Bronchopulmonary dysplasia (BPD), the most common complication of extreme preterm birth, can be caused by oxygen-related lung injury and is characterized by impaired alveolar and vascular development. Mesenchymal stromal cells (MSCs) have lung protective effects. Conversely, BPD is associated with increased MSCs in tracheal aspirates. Objective: To determine whether endogenous lung (L-)MSCs are perturbed in a well-established oxygen-induced rat model mimicking BPD features. Methods: Rat pups were exposed to room air or 95% oxygen from birth to postnatal day 10. On day 12, CD146+ L-MSCs were isolated and characterized according to the International Society for Cellular Therapy criteria. Epithelial and vascular repair potential were tested by scratch assay and endothelial network formation respectively, immune function by mixed lymphocyte reaction assay. Microarray analysis was performed using the Affymetrix GeneChip and gene set enrichment analysis (GSEA) software. Results: CD146+ L-MSCs isolated from rat pups exposed to hyperoxia had decreased CD73 expression and inhibited lung endothelial network formation. CD146+ L-MSCs indiscriminately promoted epithelial wound healing and limited T-cell proliferation. Expression of potent anti-angiogenic genes of the axonal guidance cue and CDC42 pathways was increased after in vivo hyperoxia, whereas genes of the anti-inflammatory JAK/STAT and lung/vascular growth promoting Fibroblast Growth Factor (FGF) pathways were decreased. Conclusions: In vivo hyperoxia exposure alters the pro-angiogenic effects and FGF expression of L-MSCs. Additionally, decreased CD73 and JAK/STAT expression suggest decreased immune function. L-MSC function may be perturbed and contribute to BPD pathogenesis. These findings may lead to improvements in manufacturing exogenous MSCs with superior repair capabilities.

2017-06-03 | GSE99633 | GEO

FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates

Project description:The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV) ionizing radiation (IR) dose-rate are not known. However, attenuated DNA damage and transient oxygen depletion are among a number of proposed models. Here, we tested whether FLASH-IR under physioxic (4% O2) and hypoxic conditions (≤2% O2) attenuates detection of genome-wide translocations relative to CONV dose rates and whether any differences identified revert under normoxic (21% O2) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), usingS. pyogenesandS. aureusCas9 “bait” DNA double strand breaks (DSBs), to measure differences in proximal deletions, inversions, and excision circles and their translocation to “prey” genome-wide DSBs generated by CONV (0.08-0.13Gy/s) and FLASH (1x102-5x106Gy/s) dose rates, under varying IR doses and oxygen tensions. Normoxic and physioxic IR exposure in HEK293T cells increased translocations at the cost of decreasing proximal repair but were indistinguishable between CONV and FLASH dose-rates. Although decreased numbers of translocations were recovered as cells transitioned to hypoxic (<2%) conditions, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in junction structures, which, for proximal repair, were increased in direct and short microhomologies. We conclude that irrespective of oxygen tension, FLASH IR dose rates produce translocations and junction structures at levels that are indistinguishable from CONV dose rates.

2023-03-29 | GSE227466 | GEO

neonatal and adult mice lung

Project description:We performed miRNA array analysis from 4 groups (neonatal lung control, neonatal lung after hyperoxia, adult lung control, adult lung after hyperoxia). We used pools of every 100ng of total RNA of three samples for each groups.

2015-07-15 | GSE70873 | GEO

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