Genome-wide mapping of NRF1 (NFE2L1) binding in HCT116 cells upon proteasome inhibition.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA944699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23866801.fastq.gz | Fastqsanger.gz | |||
| SRR23866802.fastq.gz | Fastqsanger.gz | |||
| SRR23866803.fastq.gz | Fastqsanger.gz | |||
| SRR23866804.fastq.gz | Fastqsanger.gz | |||
| SRR23866805.fastq.gz | Fastqsanger.gz |
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Project description:The maintenance of protein homeostasis is an essential characteristic of life. Transcription factor NRF1 (NFE2L1) has been reported to be activated by proteasome dysfunction, although the genome-wide target genes are poorly understood. Using ChIP-seq analysis, we found a potential association between NRF1 and autophagy. Our findings highlight the new activation mechanism of autophagy through gene regulation under proteasome dysfunction.
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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.
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Project description:NRF1 was localized at promoter regions of almost all proteasome subunit genes
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Project description:Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) in mammals and might play an important role in human obesity and energy homeostasis. Recent single-cell/nucleus RNA-sequencing studies have revealed heterogeneity in thermogenesis among brown adipocytes, such as the findings of low thermogenesis and regulated thermogenesis in brown adipocytes. Activating and enhancing function adipocytes (BAC) has acquired attention as a possible therapeutic intervention for metabolic diseases. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of multiple cellular functions and responds to various stress in many cells and tissues. NFE2L1 acts as a guardian role in BAC function providing increased proteometabolic quality control for adapting to cold or obesity. Our previous studies demonstrated that NFE2L1-dependent lipolytic activity is crucial for white adipose tissue (WAT) plasticity and lipid homeostasis. To further clarify the role of NFE2L1 in adipocytes, we focused on the phenotype and gene expression profiling of BAT in adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice. We found that deletion of Nfe2l1 decreased core body temperature and cold intolerance under cold exposure. Compared with floxed mice, the BAT of Nfe2l1(f)-KO mice expressed substantially lower levels of many genes related to lipolysis, thermogenesis, oxidative capacity of mitochondria, cellular respiration while higher genes related to inflammation, pyroptosis. By snRNA-seq, we found that Nfe2l1-knockout resulted in increased antigen processing and presentation (APP), necroptosis and NOD-like receptor signal pathway (NOD) signaling pathways in most subpopulations of BAC, with devastating effects on a normal subpopulation of BAC with low thermogenesis and high necroptosis genes expression. Absent of Nfe2l1 impairs the function of BAC, causing a morphological “whitening” phenotype with adipocyte hypertrophy and severe inflammation. Moreover, the adipose inflammation and pyroptosis in Nfe2l1(f)-KO mice could be mitigated by cold exposure or β3-agonist treatment. These findings provided a deeper insight into the function of NFE2L1 in the metabolic programming of brown adipocytes.
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Project description:Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) in mammals and might play an important role in human obesity and energy homeostasis. Recent single-cell/nucleus RNA-sequencing studies have revealed heterogeneity in thermogenesis among brown adipocytes, such as the findings of low thermogenesis and regulated thermogenesis in brown adipocytes. Activating and enhancing function adipocytes (BAC) has acquired attention as a possible therapeutic intervention for metabolic diseases. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of multiple cellular functions and responds to various stress in many cells and tissues. NFE2L1 acts as a guardian role in BAC function providing increased proteometabolic quality control for adapting to cold or obesity. Our previous studies demonstrated that NFE2L1-dependent lipolytic activity is crucial for white adipose tissue (WAT) plasticity and lipid homeostasis. To further clarify the role of NFE2L1 in adipocytes, we focused on the phenotype and gene expression profiling of BAT in adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice. We found that deletion of Nfe2l1 decreased core body temperature and cold intolerance under cold exposure. Compared with floxed mice, the BAT of Nfe2l1(f)-KO mice expressed substantially lower levels of many genes related to lipolysis, thermogenesis, oxidative capacity of mitochondria, cellular respiration while higher genes related to inflammation, pyroptosis. By snRNA-seq, we found that Nfe2l1-knockout resulted in increased antigen processing and presentation (APP), necroptosis and NOD-like receptor signal pathway (NOD) signaling pathways in most subpopulations of BAC, with devastating effects on a normal subpopulation of BAC with low thermogenesis and high necroptosis genes expression. Absent of Nfe2l1 impairs the function of BAC, causing a morphological “whitening” phenotype with adipocyte hypertrophy and severe inflammation. Moreover, the adipose inflammation and pyroptosis in Nfe2l1(f)-KO mice could be mitigated by cold exposure or β3-agonist treatment. These findings provided a deeper insight into the function of NFE2L1 in the metabolic programming of brown adipocytes.
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Project description:While adipocytes are critical pillars of energy metabolism, their dysfunction is linked to adipose tissue (AT) inflammation, insulin resistance, and ectopic lipotoxicity in cardiometabolic diseases. However, he mechanisms causing adipocyte inflammation and insulin resistance remain unclear. Here, we show that excess cholesterol induces adipocyte dysfunction, which is suppressed by the transcription factor Nfe2l1 (nuclear factor erythroid derived-2, like-1). Nfe2l1 is required to sustain proteasome function in adipocytes and proteotoxic stress induces adipocyte inflammation via the activation of Atf3. In humans, the Nfe2l1-proteasome pathway is inversely correlated to body mass index (BMI) in an adipose-depot specific manner. In mice, loss of adipocyte Nfe2l1 caused AT inflammation with a pronounced infiltration of macrophages and T cells. Mice lacking adipocyte Nfe2l1 displayed severe adipocyte dysfunction during diet-induced obesity (DIO), characterized by lower adipokine levels, steatosis, glucose intolerance and insulin resistance. Nfe2l1ΔAT mice on an Apoe-deficient (Apoe-/-) background fed a cholesterol-rich Western Diet (WD), developed a lipoatrophy-like syndrome, dyslipidemia, and enhanced atherosclerosis. Our results reveal an important role for proteasome-mediated proteostasis in adipocytes and indicate that Nfe2l1 is linked to metabolic health in humans and preclinical mouse models. Promoting proteostasis in adipocytes may thus alleviate inflammation in obesity, potentially averting adverse cardiometabolic outcomes.
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Project description:DNA-damage inducible 1 homolog 2 (DDI2) is an aspartic protease that cleaves and activates the transcription factor NRF1. Cellular models have shown that this pathway contributes to cell-stress adaption, for example, upon proteasome inhibition. However, DDI2 physiological function is unknown. Ddi2 Knock-out (KO) mice are embryonic lethal. However, we found that liver-specific Ddi2-KO animals are viable. We used comprehensive genetic analysis to identify the molecular pathways regulated by DDI2. We show that DDI2 mediates metallothionein (MT) expression in mouse and human hepatocytes in response to cadmium (Cd). Cd exposure inhibits the proteasome activity, resulting in NRF1 accumulation in the cytoplasm, followed by cleavage by DDI2 and translocation to the nucleus to activate MTs. Depleting DDI2 or NRF1 by CRISPR/Cas9 impaired MTs activation and sensitized the cells to Cd or cisplatin toxicity. This study identifies a new function for DDI2 that links proteasome homeostasis to heavy metal mediated toxicity.
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