Similar Datasets
Project description:The retina, the accessible part of the central nervous system, has served as a model system to study the relationship between energy utilization and metabolite supply. When the metabolite supply cannot match the energy demand, retinal neurons are at risk of death. As the powerhouse of eukaryotic cells, mitochondria play a pivotal role in generating ATP, produce precursors for macromolecules, maintain the redox homeostasis, and function as waste management centers for various types of metabolic intermediates. Mitochondrial dysfunction has been implicated in the pathologies of a number of degenerative retinal diseases. It is well known that photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and susceptibility to oxidative stress. However, it is unclear how defective mitochondria affect other retinal neurons. Nuclear respiratory factor 1 (Nrf1) is the major transcriptional regulator of mitochondrial biogenesis, and loss of Nrf1 leads to defective mitochondria biogenesis and eventually cell death. Here, we investigated how different retinal neurons respond to the loss of Nrf1. We provide in vivo evidence that the disruption of Nrf1-mediated mitochondrial biogenesis results in a slow, progressive degeneration of all retinal cell types examined, although they present different sensitivity to the deletion of Nrf1, which implicates differential energy demand and utilization, as well as tolerance to mitochondria defects in different neuronal cells. Furthermore, transcriptome analysis on rod-specific Nrf1 deletion uncovered a previously unknown role of Nrf1 in maintaining genome stability.
2022-12-17 | GSE150258 | GEO
Project description:Purpose: the goal of this experiment was to identify differentially expressed genes in Six3 null, Six6 null and Six3;Six6 compound null retinas by RNAsequencing. Method: Retinas were dissected out from the following E13.5 mouse embryos: 1) WT (Six3F/F; Six6+/+); 2) Six3 KO (Six3F/F; CAGGCre-ERTM; Six6+/+); 3) Six6 KO (Six3F/F; Six6–/–); 4) DKO (Six3F/F; CAGGCre-ERTM; Six6–/–). RNA was then extracted from the retinas and profiled using RNAsequencing. Results: RNA isolated from three pairs of retinas for each genotype group (181.2-792 ng, RIN>9) was used for library preparation using KAPA RNA HyperPrep Kit with RiboErase. Sequencing was run on Illumina HiSeq 2500 in 100-bp single-end high-output mode in the Einstein Epigenomics Core Facility. About 30 million reads were generated for each sample. Each genotype group initially had three biological replicates, but one Six6 KO replicate was later removed due to over duplication. After trimming adapters with Trim Galore (v. 0.3.7), RNA-Seq reads were aligned back to mouse genome mm10 using Tophat (v. 2.0.13). The number of reads mapped back to each gene was calculated with HTseq (v.0.6.1) using Refseq gene annotation (downloaded from the UCSC genome browser in 03/17). The Cuffdiff in Cufflinks package (v. 2.2.1) was used to generate FPKM values. We identified 13498 transcripts with FPKM value >1 in at least one of samples. Deseq2 was used to determine the differentially expressed genes (DEGs) with FDR less than 0.05 as a cutoff.
2018-11-14 | GSE115258 | GEO
Project description:This study will reveal the importance of nrf1 in revealing the translational control of Fe homeostasis
2019-12-30 | E-MTAB-8158 | biostudies-arrayexpress
Project description:Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylationsensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions. DNase-seq (2 replicates) in mouse embryonic stem cells with (WT) and without DNA methylation (DNMT TKO). RNA-seq (3 replicates) in WT and DNMT TKO cells and in DNMT TKO cells after treatment with control siRNA or siRNA targeting Nrf1. H3K27ac ChIP-seq (2 replicates) in WT and DNMT TKO cells. NRF1 ChIP-seq (2 replicates) in WT and DNMT TKO cells, in WT upon culture in different conditions (adaptation to 2i and back to serum), upon transient overexpression of NRF1 and after differentiation into neuronal progenitor cells (NP). Whole-genome bisulfite sequencing in DNMT TKO cells and in WT upon culture in different conditions (adaptation to 2i and back to serum). NRF1 ChIP-seq (2 replicates) in human HMEC and HCC1954 cells.
2015-12-16 | E-GEOD-67867 | biostudies-arrayexpress
Project description:To investigate the role of NRF1 in regulating primordial germ cell development, We established conditional knockout mice of Nrf1 in primordial germ cell to observe the effect of Nrf1 knockout on the development of primordial germ cell. At the same time, we utilized a pluripotent stem cell differentiation system in vitro to obtain PGCL cells for chip_ Seq, analyze which genes Nrf1 directly binds to. Meanwhile, we established a pluripotent stem cell line induced by Nrf1 overexpression and performed RNA_seq analysis on PGCL cells overexpressing Nrf1 obtained in vitro
2023-08-05 | GSE231662 | GEO
Project description:To investigate the role of NRF1 in regulating primordial germ cell development, We established conditional knockout mice of Nrf1 in primordial germ cell to observe the effect of Nrf1 knockout on the development of primordial germ cell. At the same time, we utilized a pluripotent stem cell differentiation system in vitro to obtain PGCL cells for chip_ Seq, analyze which genes Nrf1 directly binds to. Meanwhile, we established a pluripotent stem cell line induced by Nrf1 overexpression and performed RNA_seq analysis on PGCL cells overexpressing Nrf1 obtained in vitro
2023-08-05 | GSE231661 | GEO
Project description: Not available
| S-EPMC6192121 | biostudies-literature
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
Project description:Charaterize NRF1 cistrome in mouse muscle
2024-03-22 | GSE252431 | GEO
Project description:The endoplasmic reticulum (ER) is a multifaceted organelle that plays an essential role in cellular processes such as protein folding, modification, and trafficking. It also acts as a proteostasis sensor and contributes to adaptation responses to maintain cellular homeostasis. The transcription factor NRF1 resides in the ER and is constantly transported from the ER to the cytosol for proteasomal degradation. However, when the proteasome function is defective, NRF1 escapes degradation and undergoes proteolytic cleavage by the protease DDI2, generating a transcriptionally active form that restores proteostasis, including proteasome function. Despite the importance of NRF1 in these processes, the mechanisms that regulate its proteolytic activation and transcriptional potential remain poorly understood. In this study, we utilized a functional molecular approach to elucidate the critical steps involved in NRF1 cleavage. Our results demonstrate that the ER is a crucial regulator of NRF1 function, orchestrating its ubiquitination by the ER-localized E3 ubiquitin ligase HRD1, a component of the ER-associated degradation (ERAD) pathway. Furthermore, we show that HRD1-mediated NRF1 ubiquitination is necessary for DDI2-mediated processing in cells. Notably, we found that the fusion of a ubiquitin moiety to NRF1 was sufficient to promote its proteolytic maturation by DDI2, thus bypassing the requirement for its trafficking to the ER. Our findings highlight the intricate mechanism by which NRF1 is activated by DDI2 and coordinates the transcriptional activity of an adaptation response in cells and suggest potential avenues for therapeutic interventions in conditions associated with proteasome impairment.
2023-09-05 | PXD041331 | Pride