Effect of the autoimmune suppressor Gadd45a on radiation biodosimetry
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ABSTRACT:
PROVIDER: PRJNA804718 | ENA |
REPOSITORIES: ENA
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Project description:Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including inflammation, can potentially obscure the predictive power of the method. The Gadd45 (growth arrest and DNA damage-inducible genes) family is composed of three members, Gadd45a, Gadd45b, and Gadd45g, that play important roles in cell growth control, differentiation, DNA repair, and apoptosis. Gadd45b and Gadd45g are important for inflammatory responses as well as mediating signals of the innate immune system, whereas Gadd45a is a negative regulator of activation-induced T cell proliferation. T cells from Gadd45a null mice are hyper-responsive to activating stimuli due to spontaneously increased p38MAPK activity. Importantly, Gadd45a-deficient mice develop an autoimmune disease, similar to human systemic lupus erythematosus, characterized by severe hematological disorders, kidney disease, and premature death. The goal of this study was to elucidate how pre-existing inflammatory condition in mice can affect radiation biodosimetry. We exposed wild-type and Gadd45a knockout C57BL/6J mice to 7 Gy x-rays and 24 h later we isolated whole blood and performed genome microarray and gene ontology analysis.
2023-10-20 | GSE196400 | GEO
Project description:Gadd45a is a stress-induced protein that causes skeletal muscle atrophy. The goal of these studies was to determine the effects of Gadd45a overexpression on mRNA levels in mouse skeletal muscle. For additional details see Ebert et al, Stress-Induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy. JBC epub. June 12, 2012. Tibialis anterior (TA) muscles from muscle-specfic ATF4 knockout mice (ATF4 mKO) were transfected with either 20 mg empty plasmid (pcDNA3) (left TA) or 20 mg pCMV-FLAG-Gadd45a (right TA) and harvested 7 days later. mRNA levels in Gadd45a-transfected muscles were normalized to levels in control transfected muscles.
2012-09-15 | E-GEOD-39196 | biostudies-arrayexpress
Project description:Gadd45a is a stress-induced protein that causes skeletal muscle atrophy. The goal of these studies was to determine the effects of Gadd45a overexpression on mRNA levels in mouse skeletal muscle. For additional details see Ebert et al, Stress-Induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy. JBC epub. June 12, 2012.
2012-09-15 | GSE39196 | GEO
Project description:Understanding the possible impact of potential confounding factors is necessary for any approach to radiation biodosimetry. Potential confounding factors have not been fully addressed for gene expression-based biodosimetry approaches, such as we are developing. To begin addressing this need, we have used an ex vivo irradiated peripheral blood cell model to investigate the potential effect of smoking on the global radiation gene expression response, and looked for genes that respond to radiation differently in smokers and non-smokers, and also in males and females. The results indicate that only a small number of genes may be significantly confounded by either factor, supporting the idea of developing peripheral blood gene expression strategies for radiation biodosimetry.
2011-03-16 | GSE23515 | GEO
Project description:Understanding the possible impact of potential confounding factors is necessary for any approach to radiation biodosimetry. Potential confounding factors have not been fully addressed for gene expression-based biodosimetry approaches, such as we are developing. To begin addressing this need, we have used an ex vivo irradiated peripheral blood cell model to investigate the potential effect of smoking on the global radiation gene expression response, and looked for genes that respond to radiation differently in smokers and non-smokers, and also in males and females. The results indicate that only a small number of genes may be significantly confounded by either factor, supporting the idea of developing peripheral blood gene expression strategies for radiation biodosimetry. Blood from each of 24 different donors was exposed to four doses of ionizing radiation (0, 0.1, 0.5, or 2 Gy) and analyzed using single-color microarray hybridization. The donors represented equal numbers of male and female smokers (1 or more packs a day) and non-smokers. There are 95 data sets in the study as the sample from one of the female smokers exposed to 2 Gy was lost.
2011-03-16 | E-GEOD-23515 | biostudies-arrayexpress
Project description:Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet) -initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway.
2015-05-07 | GSE62496 | GEO
Project description:Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet) -initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway. The dataset includes RRBS anlysis of 2 WT ES cell samples and 2 Gadd45a/b DKO ES cell samples.
2015-05-07 | E-GEOD-62496 | biostudies-arrayexpress
Project description:Gadd45a can enhance somatic cell reprogramming significantly. To explore the roles of Gadd45a playing in reprogramming, we performed miRNA microarray to identify miRNAs and signals pathways that regulated by Gadd45a.
2014-04-22 | GSE56942 | GEO
Project description:Gadd45a can enhance somatic cell reprogramming significantly. To explore the roles of Gadd45a playing in reprogramming, we performed whole genome microarray to identify genes and signals pathways that regulated by Gadd45a.
2014-04-22 | GSE56943 | GEO
Project description:To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish radiation dose across an exposure range relevant for medical decision-making in a radiological emergency. Human peripheral blood from healthy donors was irradiated ex vivo, and a 74-gene consensus signature was identified that distinguished between four radiation doses (0.5, 2, 5 and 8 Gy) and control samples. The same set of genes separated samples by exposure level at both six and 24 hours after treatment, with overlap evident only at the highest two doses (5 and 8 Gy). Expression of five genes (CDKN1A, FDXR, SESN1, BBC3 and PHPT1) from this signature was quantified in the same RNA samples by real-time PCR, confirming low variability between donors as well as the predicted radiation response pattern. Keywords: Dose Response, stress response, radiation response, biodosimetry
2008-07-01 | GSE8917 | GEO