Defining the Functional Targets of Cap’n’collar Transcription Factors NRF1, NRF2, and NRF3.
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ABSTRACT:
PROVIDER: PRJNA668112 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12795553.fastq.gz | Fastqsanger.gz | |||
| SRR12795554.fastq.gz | Fastqsanger.gz | |||
| SRR12795555.fastq.gz | Fastqsanger.gz | |||
| SRR12795556.fastq.gz | Fastqsanger.gz | |||
| SRR12795557.fastq.gz | Fastqsanger.gz |
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Project description:The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap’n’collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their genetic targets remains incompletely defined. Here we use RNA-sequencing-based transcriptional profiling and quantitative proteomics to delineate the overlapping and differential genetic programs effected by the three NRF transcription factors. Comparing our data to recent profiling analyses, we create consensus target gene sets regulated by NRF1, NRF2, and NRF3, genetic programs which we determine to be differentially regulated in human tissues. Together, our data provide a quantitative assessment of how NRF family members sculpt proteomes and transcriptomes, essential information for future studies evaluating the role of NRF factors in normal physiology and disease.
2020-10-21 | GSE159230 | GEO
Project description:The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap'n'collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their genetic targets remains incompletely defined. Here we use RNA-sequencing-based transcriptional profiling and quantitative proteomics to delineate the overlapping and differential genetic programs effected by the three NRF transcription factors. We then create consensus target gene sets regulated by NRF1, NRF2, and NRF3 and define the integrity of these gene sets for probing NRF activity in mammalian cell culture and human tissues. Together, our data provide a quantitative assessment of how NRF family members sculpt proteomes and transcriptomes, providing a framework to understand the critical physiological importance of NRF transcription factors and to establish pharmacologic approaches for therapeutically activating these transcriptional programs in disease.
| S-EPMC7588902 | biostudies-literature
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: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: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: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)-like (NRF) transcription factors are a subset of cap'n'collar transcriptional regulators. They consist of three members, NRF1, NRF2, and NRF3, that regulate the expression of genes containing antioxidant-response elements (AREs) in their promoter regions. Although all NRF members regulate ARE-containing genes, each is associated with distinct roles. A comprehensive study of differential and overlapping DNA-binding and transcriptional activities of the NRFs has not yet been conducted. Here, we performed chromatin immunoprecipitation (ChIP)-exo sequencing, an approach that combines ChIP with exonuclease treatment to pinpoint regulatory elements in DNA with high precision, in conjunction with RNA-sequencing to define the transcriptional targets of each NRF member. Our approach, done in three U2OS cell lines, identified 31 genes that were regulated by all three NRF members, 27 that were regulated similarly by all three, and four genes that were differentially regulated by at least one NRF member. We also found genes that were up- or down-regulated by only one NRF member, with 84, 84, and 22 genes that were regulated by NRF1, NRF2, and NRF3, respectively. Analysis of the ARE motifs identified in ChIP peaks revealed that NRF2 prefers binding to AREs flanked by GC-rich regions and that NRF1 prefers AT-rich flanking regions. Thus, sequence preference, likely in combination with upstream signaling events, determines NRF member activation under specific cellular contexts. Our analysis provides a comprehensive description of differential and overlapping gene regulation by the transcriptional regulators NRF1, NRF2, and NRF3.
| S-EPMC6885608 | biostudies-literature
Project description:Transcription factor NRF1 (NFE2L1) has been reported to be activated by proteasome disfunction, although the target genes are poorly understood. We used microarrays to identify NRF3-regulated gene expression network related to proteostasis.
2023-03-18 | GSE227232 | 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 | PXD043248 | 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 | PXD043182 | Pride