Ontology highlight
ABSTRACT:
PROVIDER: PRJNA806849 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18506000.fastq.gz | Fastqsanger.gz | |||
| SRR18506001_1.fastq.gz | Fastqsanger.gz | |||
| SRR18506001_2.fastq.gz | Fastqsanger.gz | |||
| SRR18506002_1.fastq.gz | Fastqsanger.gz | |||
| SRR18506002_2.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic-associated steatohepatitis is a progressive fatty liver disease caused, in part, by hepatocyte stress linked to cholesterol overload. Counteracting this stress may be beneficial but there is insufficient understanding of underlying stress defenses to develop a therapeutic strategy. Here, we aimed to elucidate how stress-adaptive transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), counteract hepatic cholesterol overload and determine whether they function cooperatively. C57bl/6 mice were fed high fat, fructose, and cholesterol diet (HFFC). Expression profiling and phenotypic analyses were done on liver of mice with adult-onset and hepatocyte-specific deficiency of NRF1, NRF2, or both, and results compared to control. Chromatin immunoprecipitation (ChIP) sequencing was done and combined with expression profiles to identify genes that NRF1 and NRF2 interact with and regulate in vivo. Three weeks HFFC diet feeding to mice with NRF1 and NRF2 deficiency caused severe steatohepatitis and increased hepatic cholesterol storage. These outcomes did not occur in single gene-deficient mice or control. Expression profiling at a time preceding hepatic cholesterol overload and ChIP sequencing profiling revealed complementary gene regulation by NRF1 and NRF2 to promote cholesterol excretion and mitigate hazardous metabolic biproducts generated from converting cholesterol to bile acid. Consequently, combined gene deficiency, and not single-gene deficiency, increased liver oxidized protein level, decreased cholesterol in bile, and increased unconjugated bile acid in liver and bile. We discover, for the first time, that NRF1 and NRF2 work together to protect liver against damaging effects of excess cholesterol. Targeting these combined actions may prove an effective therapeutic strategy
2023-03-22 | PXD032069 | Pride
Project description:High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL. Liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. Mechanisms linking liver stress to HDL functionality are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2) promote hepatocyte production of functional HDL. Using genetically engineered mouse models briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of NRF1, NRF2, or both on circulating HDL cholesterol level, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol content as well as the capacity of HDL to accept cholesterol efflux from cultured macrophages and to counteract tumor necrosis factor a-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the circulating HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Altogether, our findings show complementary actions by hepatocyte NRF1 and NRF2 play a role in shaping HDL composition and promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.
2023-07-03 | PXD042103 | Pride
Project description:Nrf/NFE2L family transcription factors regulate redox balance, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. The closely related Nrf2/NFE2L2 is responsible for activation of oxidative stress responses and xenobiotic detoxification. Although regulated by different mechanisms, Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. However, the extent to which functions of Nrf1/2 are distinct or overlapping has been unclear. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively. We previously showed that regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term ‘sequence editing’. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We show that whilst activation of proteasome subunit genes is strictly dependent on sequence editing, sequence edited SKN-1A also activate genes linked to redox homeostasis and xenobiotic detoxification that are also activated by non-sequence edited forms of SKN-1. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that SKN-1A/Nrf1 and SKN-1C/Nrf2 function coordinately to promote optimal oxidative stress resistance and confirm that they are regulated by discrete genetic pathways. This work demonstrates that sequence editing plays a critical role in tailoring SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.
2025-06-17 | GSE279082 | GEO
Project description:To identify Nrf1-dependent and Nrf2-dependent genes in the liver, we examined the gene expression profiles of Nrf1 Alb-CKO, Nrf2 knockout and Keap1 knockdown mouse livers by microarray analyses. Total RNAs from Nrf1dN/-::Alb-Cre, Nrf1dN/+, Nrf2-/-, Nrf2+/+, Keap1KD/- and Keap1KD/+ mouse livers were used for the microarray analyses.
2012-05-17 | E-GEOD-35124 | biostudies-arrayexpress
Project description:To identify Nrf1-dependent and Nrf2-dependent genes in the liver, we examined the gene expression profiles of Nrf1 Alb-CKO, Nrf2 knockout and Keap1 knockdown mouse livers by microarray analyses.
2012-05-18 | GSE35124 | GEO
Project description:The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. In disease, constitutive NRF2 activity promotes cancer progression while decreased NRF2 function contributes to neurodegenerative diseases. In contrast to the regulation of NRF2 protein stability in the cytoplasm, co-complexed proteins that govern NRF2 activity on chromatin are less clear. Using biotin proximity proteomics, we report networks for NRF2 and its family members NRF1, NRF3 and the NRF2 heterodimer MAFG. We found that the Parkinson’s disease zinc finger transcription factor ZNF746 (PARIS) physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 expression increased oxidative stress and apoptosis, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests that ZNF746 overexpression in Parkinson’s disease directly inhibits NRF2-driven neuroprotection
2023-12-18 | PXD043182 | Pride
Project description:The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. In disease, constitutive NRF2 activity promotes cancer progression while decreased NRF2 function contributes to neurodegenerative diseases. In contrast to the regulation of NRF2 protein stability in the cytoplasm, co-complexed proteins that govern NRF2 activity on chromatin are less clear. Using biotin proximity proteomics, we report networks for NRF2 and its family members NRF1, NRF3 and the NRF2 heterodimer MAFG. We found that the Parkinson’s disease zinc finger transcription factor ZNF746 (PARIS) physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 expression increased oxidative stress and apoptosis, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests that ZNF746 overexpression in Parkinson’s disease directly inhibits NRF2-driven neuroprotection.
2023-12-18 | PXD043248 | Pride
Project description:The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 8 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated that the suppression of Keap1 expression induced genes that are involved in anti-oxidative stress defense and biotransformation, pathways proving the activation of Nrf2 by the siRNAs against Keap1. The expression of neither fatty acid- nor carbohydrate-handling proteins was regulated by the suppression of Keap1. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance by the activation of Nrf2. The data indicate that hepatic Nrf2 is not a major regulator of intermediary metabolism in mice. Gene expression profile of mouse liver samples from 8-week-old male C57BL6/J mice (N=24) treated with liver-selective Keap1-specific siRNA (group 1: siKeap1-1, N=8; group 2: siKeap1-2, N=8) or unspecific scrambled control siRNA (group 3: siControl, N=8)
2016-09-01 | E-GEOD-80956 | biostudies-arrayexpress
Project description:Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic oxidative stress following activation of the aryl hydrocarbon receptor (AhR). Our recent studies revealed induction of pyruvate kinase muscle isoform 2 (Pkm2) as a novel antioxidant response in normal differentiated hepatocytes. To investigate cooperative regulation between nuclear factor, erythroid derived 2, like 2 (Nrf2) and the AhR, hepatic ChIP-seq analyses were integrated with RNA-seq time course data from mice treated with TCDD for 2 - 168h. ChIP-seq analysis 2h following TCDD treatment revealed genome-wide changes in NRF2 binding. 842 NRF2 enriched regions were in the regulatory region of differentially expressed genes (DEGs) while 579 DEGs showed both NRF2 and AhR enrichment. Sequence analysis showed over-representation of AhR and NRF2 binding motifs in these regions, though presence of motifs were largely independent. NRF2 was negligibly enriched within the Pkm gene loci in a closed chromatin region despite its role in antioxidant defenses. Furthermore, TCDD induced Pkm2 in primary hepatocytes from wild-type and Nrf2 null mice, indicating NRF2 is not required. Although NRF2 and AhR cooperate in the regulation of gene expression associated with antioxidant responses, the induction of Pkm2 by TCDD is not dependent on ROS-mediated activation of NRF2.
2018-06-07 | GSE109865 | GEO
Project description:Purpose: Next-generation sequencing (NGS) for systematic analysis to discover Nrf1-dependent cellular pathways involved in defending liver against the stress of cholesterol excess. Methods: Liver mRNA profiles of 9-12-old wild-type (WT in fastq files; flox in paper) and liver Nrf1 deficient (KO in fastq files; L-KO in paper) mice were generated by deep sequencing, in triplicate or quadruplicate, using Illumina HiSeq2500. The sequence reads that passed quality filters were analyzed at the transcript level with TopHat followed by Cufflinks. qRT–PCR validation of selected target genes was performed using SYBR Green assays. Results: We mapped sequence reads to the mouse genome (build mm10) and identified greater than 10,000 transcripts in the liver of WT and KO mice. RNA-seq data revealed a role for Nrf1 in regulating inflammation, lipid metabolism, and sterol metabolism in response to a cholesterol challenge. Conclusion: Our study reveal Nrf1 as a guardian of cholesterol homeostasis and a core component of adaptive responses to excesses in cellular cholesterol.
2017-11-30 | GSE103949 | GEO