PCB126 (3,3',4,4',5-Pentachlorobiphenyl) induced alterations in m6A RNA modifications in zebrafish embryos
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA642647 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12103768_1.fastq.gz | Fastqsanger.gz | |||
| SRR12103768_2.fastq.gz | Fastqsanger.gz | |||
| SRR12103769_1.fastq.gz | Fastqsanger.gz | |||
| SRR12103769_2.fastq.gz | Fastqsanger.gz | |||
| SRR12103770_1.fastq.gz | Fastqsanger.gz |
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Project description:Chemical modifications of proteins, DNA and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests these RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N6-methyladenosine (m6A). In a subset of mammalian mRNAs, m6A sites are preferentially enriched near stop codons, in 3′ UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6 hours starting from 72 hours post-fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq), as well as assessing changes in mRNA splicing. We observed several hundreds of peaks that are differentially expressed in response to PCB126 exposure (FDR 5%). The majority of the peaks are preferentially located around the 3’UTR and stop codons. Pathway analysis of m6A marked transcripts induced by PCB126 exposure revealed that these transcripts are associated with important developmental pathways (MAPK, Hedgehog, Notch and Wnt). These results suggest that PCB126 could affect developmental gene expression patterns by altering m6A levels. Gene expression analysis revealed upregulation of classical aryl hydrocarbon receptor (AHR) target genes such as cytochrome P450s in response to PCB126 exposure. Interestingly, none of the AHR target genes overlapped with the m6A altered transcripts, suggesting that xenobiotic metabolism may not be under m6A regulation. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels. This work is supported by NIEHS ES024915.
2020-06-29 | GSE153436 | GEO
Project description:Exposure to polychlorinated biphenyls (PCBs) has been associated with liver injury in human cohorts and with nonalcoholic steatohepatitis (NASH) in mice fed a high fat diet (HFD). N(6)-methyladenosine (m6A) modification of mRNA regulates transcript fate, but the contribution of m6A modification on regulation of transcription in PCB-induced steatosis and fibrosis is unknown. This study tested the hypothesis that PCB and HFD exposure alters the levels of m6A modification in transcripts that play a role in NASH in vivo. Male C57Bl6/J mice were fed a HFD (12 wks.) and administered a single oral dose of Aroclor1260, PCB126, or Aroclor1260 + PCB126. Genome-wide identification of m6A peaks was accomplished by m6A mRNA immunoprecipitation sequencing (m6A-RIP) and the mRNA transcriptome identified by RNA-seq. Exposure of HFD-fed mice to Aroclor1260 decreased the number of m6A peaks and m6A-containing genes relative to HFD control whereas PCB126 or the combination of Aroclor1260+PCB126 increased m6A modification frequency. ~ 41% of genes had one m6A peak and ~49% had 2-4 m6A peaks. 117 m6A peaks were common in the four experimental groups. The Aroclor1260 + PCB126 exposure group showed the highest number (52) of m6A-peaks. qRT-PCR confirmed enrichment of m6A-containing fragments of the Apob transcript with PCB exposure. Integrated analysis of m6A-RIP-seq and mRNA-seq identified 242 differentially expressed genes (DEGs) with increased or reduced number of m6A peaks. Comparative pathway analysis identified “Immune response: IL-6-induced acute-phase response in hepatocytes” in the Aroclor1260 + PCB126 samples, consistent with steatohepatitis in human PCB epidemiological studies. These data show that PCB exposure in HFD-fed mice alters the m6A landscape offering an additional layer of regulation of gene expression affecting a subset of gene responses in NASH.
2023-05-12 | GSE202386 | GEO
Project description:Chemical modifications of proteins, DNA, and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests the RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N6-methyladenosine (m6A). In a subset of mRNAs, m6A sites are preferentially enriched near stop codons, in 3' UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6 h starting from 72 h post fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq). Our analysis revealed 117 and 217 m6A peaks in the DMSO and PCB126 samples (false discovery rate 5%), respectively. The majority of the peaks were preferentially located around the 3' UTR and stop codons. Statistical analysis revealed 15 m6A marked transcripts to be differentially methylated by PCB126 exposure. These include transcripts that are known to be activated by AHR agonists (eg, ahrra, tiparp, nfe2l2b) as well as others that are important for normal development (vgf, cebpd, sned1). These results suggest that environmental chemicals such as dioxin-like PCBs could affect developmental gene expression patterns by altering m6A levels. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels.
| S-EPMC8453794 | biostudies-literature
Project description:The objective of this study is to determine the effects of pre-conceptional exposure to environmental chemicals on DNA methylation and gene expression in testis. We used a dioxin-like PCB (3, 3’, 4, 4’, 5-pentachlorobiphenyl; PCB126) as a model environmental chemical because the mechanism of action is well-characterized, involving activation of aryl hydrocarbon receptor, a ligand-activated transcription factor. Adult zebrafish were exposed to 3 and 10 nM PCB126 for 24 h (water-borne exposure) and testis tissue was sampled at 7 days post-exposure for histology, DNA methylation and gene expression profiling. We used enhanced Reduced Representation Bisulfite Sequencing (RRBS) and RNAseq to quantify DNA methylation and gene expression, respectively. RRBS revealed 37 and 92 differentially methylated regions (DMRs) in response to 3 and 10nM PCB126 exposures, respectively. We observed 19 DMRs to be common between the two PCB126 treatment groups. Among them 14 and 5 are hypomethylated and hypermethylated, respectively. Majority of these DMRs are hypomethylated and gene ontology analysis revealed that these regions are regulate genes associated with RNA processing, nucleoside metabolic process, iron-sulfur cluster assembly and gluconeogenesis. Dysregulation of all these pathways have been associated with spermatogenic defects such as infertility. RNAseq results revealed differential expression of genes related to xenobiotic metabolism, oxidative stress and immune function. There was very little correlation between differentially methylated regions and differentially expressed genes suggesting complex and multiple layers of regulation. Overall, the results from this study provide new understanding about the mechanisms of action of dioxin-like PCBs in affecting testicular function and potential multigenerational phenotypes.
2021-12-15 | GSE190741 | GEO
Project description:Early life exposure to low levels of AHR agonist 3,3’,4,4’,5-pentachlorobiphenyl (PCB126) reprograms gene expression in adult brain.
| PRJNA386102 | ENA
Project description:Purpose: The goal of this study was to perform an expression transcript profile over a timecourse of human preadipocytes that were treated with PCB126; Methods: Immortal human preadipocytes (NPAD) were treated with 10 uM PCB126 for 9 hrs, 1 day, or 3 days. RNA was extracted with TriZol, DNase treated, and purified using a Qiagen column. RNAseq was used to assess gene expression. Bioinformatic analyses were used to determine differential gene expression between PCB126 treated and vehicle-treated at the same timepoint.
2022-05-24 | GSE193578 | GEO
Project description:This study investigates the effects of the aryl hydrocarbon receptor (AhR) ligands TCDD, PCB126 and PeCDF; the non-AhR ligand PCB153 and the binary mixture PCB126/PCB153 on hepatic gene expression in female sprague dawley rats. Rats were treated with toxicological equivalent doses of TCDD (100ng/kg), PeCDF (200ng/kg), PCB126 (1000ng/kg) and PCB153 (1000ug/kg) 5 days a week for 13 weeks. Experiment Overall Design: There are 6 control chips and representing animals treated with vehicle control. There are 3 biological replicates (3 chips) for each treatment group (eg. TCDD, PCB126), each biological replicate is derived from 2 individual animals. A total of 21 chips were analyzed. Intensities were normalized using the GC-Robust Multiarray (GCRMA) method through Genetraffic software package.
2008-06-14 | E-GEOD-5789 | biostudies-arrayexpress
Project description:This study investigates the effects of the aryl hydrocarbon receptor (AhR) ligands TCDD, PCB126 and PeCDF; the non-AhR ligand PCB153 and the binary mixture PCB126/PCB153 on hepatic gene expression in female sprague dawley rats. Rats were treated with toxicological equivalent doses of TCDD (100ng/kg), PeCDF (200ng/kg), PCB126 (1000ng/kg) and PCB153 (1000ug/kg) 5 days a week for 13 weeks. Keywords: Environmental pollutant toxicity comparison
2006-09-08 | GSE5789 | GEO
Project description:Background: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been shown to alter and promote the development of alcohol-associated liver disease (ALD). Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in an ALD rodent model. Objectives: To better understand how PCB126 promoted ALD, the current study adopts transcriptomic and metallomic approaches to identify mechanistic pathways involved in this promotion. Methods: Briefly, male C57BL/6J mice were exposed to 0.2 mg/kg PCB126 or corn oil vehicle prior to ethanol feeding in the chronic-binge model. Liver tissues were collected for RNA sequencing and ICP-MS metals quantification. Results: PCB126 uniquely modified the transcriptome in EtOH-fed mice in terms of variance. EtOH feeding alone resulting in >4000 differentially expressed genes (DEGs) and PCB126 exposure resulted in more DEGs in the EtOH-fed group over the pair-fed group. Top gene ontology (GO) biological processes indicated ‘peptidyl tyrosine modifications’ and GO molecular function processes showed a loss of ‘metal, and ion, and zinc binding’. Western blot analysis depicted that the JAK2-STAT5 signaling axis was disrupted by the enhanced loss of phosphorylated JAK2 in EtOH+PCB126 mice. Quantified liver essential metal levels were overall depleted by EtOH feeding, and potassium, magnesium, cobalt, and zinc were further decreased by PCB126. Discussion: The results suggests that phosphorylation and metal binding are disrupted in EtOH+PCB126 mice, implying that evolutionarily conserved homeostatic signaling mechanisms are modified by pollutant exposure in EtOH-fed mice. The loss of phosphorylation and essential metals are two suggestive modes of action that may explain the promotion of disease by PCB126 in ALD.
2024-05-01 | GSE244388 | GEO
Project description:N6-methyladenosine (m6A) is a widespread reversible chemical modification of RNAs, implicated in many aspects of RNA metabolism. Little quantitative information exists as to either how many transcript copies of particular genes are m6A modified (âm6A levelsâ), or the relationship of m6A modification(s) to alternative RNA isoforms. To deconvolute the m6A epitranscriptome, we developed m6A level and isoform-characterization sequencing (m6A-LAIC-seq). We found that cells exhibit a broad range of non-stoichiometric m6A levels with cell type specificity. At the level of isoform characterization, we discovered widespread differences in use of tandem alternative polyadenylation (APA) sites by methylated and nonmethylated transcript isoforms of individual genes. Strikingly, there is a strong bias for methylated transcripts to be coupled with proximal APA sites, resulting in shortened 3â untranslated regions (3â-UTRs), while nonmethylated transcript isoforms tend to use distal APA sites. m6A-LAIC-seq yields a new perspective on transcriptome complexity and links APA usage to m6A modifications. m6A-LAIC-seq of H1-ESC and GM12878 cell lines, each cell line has two replicates
2016-06-24 | E-GEOD-66086 | biostudies-arrayexpress