Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

Yu, Feng; Tian, Jianhui; Krylova, Irina; Xu, Tuan; Xie, Heidi Qunhui; Guo, Tai L.; Zhao, Bin

doi:10.1016/j.jes.2015.11.011

Cited by 8 publications

(6 citation statements)

References 64 publications

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“…41 Clinically, the presence of lymphadenopathy predicts future lymphoma risk, 42 and transcriptomic analysis has revealed CREM as a top upstream transcriptional regulator of molecular signatures associated with lymphomagenic transdifferentiation. 43 Furthermore, methotrexate and biologics reduce CREM expression (Figure 2A,F), and several cohort studies have reported protective effects of methotrexate and biologics on lymphoma. 44,45 Therefore, it is likely that CREM is also involved in the development of lymphoma in RA.…”

Section: Discussionmentioning

confidence: 86%

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis

Tseng

Lin

et al. 2022

Eur J Clin Investigation

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Background: Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune-mediated inflammatory processes, although it remains unknown whether CREM is involved in RA.Methods: This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real-time polymerase chain reaction.The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing.Differences between groups and correlations between variables were assessed with Student's t-tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression.Results: Rheumatoid arthritis patients exhibited increased CREM expression (p < .0001), which was decreased by methotrexate (p = .0223) and biologics (p = .0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p = .0377), and rs1213386 increased the risk of lymphadenopathy (p = .0398). Furthermore, seven CpG sites showed decreased methylation in RA (p = .0477~ p < .0001).

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Section: Discussionmentioning

confidence: 86%

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis

Tseng

Lin

et al. 2022

Eur J Clin Investigation

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“…transcription, translation, and replication) and cell signaling, growth and differentiation, metabolism, division, protein synthesis, and so on. Throughout their whole life, cells are doomed to undergo a variety of exogenous stresses and pathological attacks (Alberts et al, 2008;Feng et al, 2016).…”

Section: Varied Environment and Complex Cell Events Results In A Dissimentioning

confidence: 99%

Epigenetics recording varied environment and complex cell events represents the origin of cellular aging

Guo

Dong

Zhang

2019

J. Zhejiang Univ. Sci. B

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Although a relationship between epigenetics and aging phenotypic changes has been established, a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking. In this essay, we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging. Through epigenetic modifications, the environment and historical events can induce the chromatin template into an activated or repressive accessible structure, thereby shaping the DNA template into a spectrum of chromatin states. The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template. This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression. An unavoidable degradation of epigenome entropy, similar to Shannon entropy, would be consequently induced. The resultant disorder in epigenome, characterized by corrosion of epigenome entropy as reflected in chromatin template, can be stably memorized and propagated through cell division. Furthermore, the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy. As well as stochastic errors, we propose that outside entropy (or chaos) derived from the varied environment and complex cell history, gradually input and imprinted into the chromatin via epigenetic modifications, would lead inevitably to cellular aging, the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.

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“…CREB1 involvement in the cAMP/PKA signaling and in the AhR signaling pathways had been previously demonstrated in multiple cell types, including in mouse B cells (Feng et al ., 2016; Landers and Bunce, 1991). Similarly, it has been previously demonstrated that in mouse primary B cells, a member of AP1 transcription factors Fra1 blocks plasma cell differentiation and IgM production by directly repressing Blimp1 expression (Grotsch et al ., 2014).…”

Section: Discussionmentioning

confidence: 95%

Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells

Kovalova

Nault

Crawford

et al. 2017

Toxicology and Applied Pharmacology

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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant that activates the aryl hydrocarbon receptor (AhR) resulting in altered gene expression. In vivo, in vitro, and ex vivo studies have demonstrated that B cells are directly impaired by TCDD, and are a sensitive target as evidenced by suppression of antibody responses. The window of sensitivity to TCDD-induced suppression of IgM secretion among mouse, rat and human B cells is similar. Specifically, TCDD must be present within the initial 12 h post B cell stimulation, indicating that TCDD disrupts early signaling network(s) necessary for B lymphocyte activation and differentiation. Therefore, we hypothesized that TCDD treatment across three different species (mouse, rat and human) triggers a conserved, B cell-specific mechanism that is involved in TCDD-induced immunosuppression. RNA sequencing (RNA-Seq) was used to identify B cell-specific orthologous genes that are differentially expressed in response to TCDD in primary mouse, rat and human B cells. Time course studies identified TCDD-elicited differential expression of 515 human, 2371 mouse and 712 rat orthologous genes over the 24-h period. 28 orthologs were differentially expressed in response to TCDD in all three species. Overrepresented pathways enriched in all three species included cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, regulation of actin cytoskeleton and pathways in cancer. Differentially expressed genes functionally associated with cell-cell signaling in humans, immune response in mice, and oxidation reduction in rats. Overall, these results suggest that despite the conservation of the AhR and its signaling mechanism, TCDD elicits species-specific gene expression changes.

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Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

Cited by 8 publications

References 64 publications

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis

Epigenetics recording varied environment and complex cell events represents the origin of cellular aging

Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells

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