关键词： ATF3   NRF2   chromatin dynamics   development   enhancers   hepatocyte   liver   regeneration   transcription factors  

摘要： The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.

关键词： Activating transcription factor 3   Apoptosis   BK polyomavirus   Cisplatin  

摘要： Recent evidence links BK polyomavirus (BKPyV) infection to an increased risk of bladder cancer. This study investigates the role of BKPyV and its microRNA, miR-B1, in cisplatin-induced apoptosis. PCR analysis detected BKPyV DNA in 3 of 22 urothelial carcinoma (UC) samples from a non-transplant population. Bladder cancer cells infected with BKPyV showed increased proliferation and miR-B1–3p and −5p expression. Bioinformatics analysis identified a miR-B1–5p target site in the 3′-UTR of activating transcription factor 3 (ATF3), confirmed by a luciferase assay. The inhibitory effect was further validated by reduced ATF3 mRNA levels following overexpression of miR-B1 vectors or 5p mimics. Cisplatin treatment upregulated ATF3 expression, as shown by qPCR and immunoblotting. Overexpression of ATF3 mitigated the cisplatin-induced reduction in cell viability and elevated apoptotic markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). BKPyV infection or large T antigen (TAg) overexpression suppressed cisplatin-induced ATF3 expression, reducing its cytotoxicity and apoptotic marker expression. However, overexpression of ATF3 in BKPyV-infected bladder cancer cells attenuated BKPyV's inhibitory effects, restoring cisplatin-induced cytotoxicity and apoptotic marker expression, suggesting BKPyV infection promotes resistance to cisplatin cytotoxicity. Transfection with miR-B1 vectors or miR-B1–5p mimics decreased cisplatin-induced annexin V-positive cells, caspase-3 activity, and apoptotic marker expression, indicating that miR-B1 suppresses cisplatin-induced apoptosis. In conclusion, this study demonstrates that BKPyV promotes bladder cancer cell growth and impairs cisplatin-induced apoptosis, with miR-B1 targeting ATF3 as a key mechanism. Targeting BKPyV replication or regulating miR-B1 expression could offer potential therapeutic strategies for managing BKPyV-positive and cisplatin-resistant urothelial carcinoma. © 2025

关键词： ATF3   ER stress   FADS1   Kidney cancer   PUFA  

摘要： Objective: Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study. Method and results: We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest. Conclusion: Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target. © 2025 The Authors

关键词： apolipoprotein A4   Atf3   fatty acid oxidation   gene knockout   liver metabolism   metabolic regulation   sex-dependent   transcription factor  

摘要： The liver plays essential roles in maintaining systemic glucolipid homeostasis under ever changing metabolic stressors. Metabolic dysregulation can lead to both adaptive and maladaptive changes that impact systemic physiology. Here, we examined disparate genetic and environmental metabolic stressors and identified apolipoprotein A4 (ApoA4) as a circulating protein upregulated in liver-specific KOs for carnitine palmitoyltransferase 2 and pyruvate carboxylase. We found this upregulation to be exacerbated by fasting and highfat or ketogenic diets. Unique among these models was a concomitant increase in activating transcription factor 3 (Atf3). ApoA4 expression in a sex-dependent manner. To understand the requirement of Atf3 to metabolic stress, we generated liverspecific Atf3, Cpt2 double KO mice. These experiments demonstrated the requirement for Atf3 in the induction of ApoA4 mRNA, ApoA4 protein, and serum triglycerides that hepatic Atf3 and ApoA4 in response to metabolic stress in vivo.

关键词： epigenetics regulation   lipid metabolism   mTORC1 signaling  

摘要： Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and a major contributor to cancer-related mortality globally. Central to its pathogenesis is the dysregulation of lipid metabolism in hepatocytes, leading to abnormal lipid accumulation. Our bioinformatics analysis has identified the histone acetyltransferase complex subunit VPS72 as being associated with HCC, yet the precise molecular mechanisms through which VPS72 contributes to hepatocarcinogenesis remain poorly understood. Our analysis of extensive HCC patient cohorts identifies a significant proportion with VPS72 copy number gains, which are strongly linked to adverse prognostic outcomes. By integrating RNA-Seq, ChIP-Seq, ATAC-seq, and experimental validation, we show that VPS72 overexpression activates mTORC1 signaling, subsequently promoting lipid synthesis and driving HCC progression. We further uncover that VPS72 modulates the epigenetic landscape by enhancing DNA methylation at the ATF3 promoter, resulting in ATF3 repression and subsequent activation of mTORC1. This study elucidates a novel regulatory axis that links dysregulated lipid metabolism with HCC progression, highlighting potential epigenetic and metabolic targets for therapeutic intervention.

关键词： Ischemic stroke   Ferroptosis   ATF3   Keap1/Nrf2/HO-1   Middle cerebral artery occlusion   Oxygen glucose deprivation/reperfusion  

摘要： Ischemic stroke is a common event of cerebrovascular disease, and inhibiting ferroptosis is associated with improvement in ischemic stroke. The purpose was to evaluate the effects of activating transcription factor 3 (ATF3) knockdown on ferroptosis in ischemic stroke and to reveal its underlying mechanism. Ischemic condition was simulated in HT22 cells by oxygen glucose deprivation/reperfusion (OGD/R), and an ischemic stroke model was induced by middle cerebral artery occlusion (MCAo) in rats. ATF3 was knocked down to investigate its effects on cerebral infarct size, cell death, oxidative stress, Fe2+ and ferroptosis, and the kelch-like ECH-Associating protein 1 (Keap1)/nuclear factor erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in HT22 cells and stroke rats. Knockdown of ATF3 decreased neurological score, increased duration on the rotarod, and decreased scores of balance beam test. Meanwhile, knockdown of ATF3 decreased infarct area, suppressed apoptosis, and improved brain structure in MCAo rats. Knockdown of ATF3 decreased the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+, increased glutathione (GSH), decreased cyclooxygenase 2 (COX2) and increased glutathione peroxidase 4 (GPX4). The levels of Nrf2 and HO-1 were upregulated while Keap1 was downregulated after knocking down ATF3. Similarly, knockdown of ATF3 alleviated ischemic condition, inhibited ferroptosis, reduced cell apoptosis, and activated the Keap1/Nrf2/HO-1 pathway in HT22 cells. ML385 reversed the effects of ATF3 knockdown on ferroptosis and Keap1/Nrf2/HO-1 pathway. Knockdown of ATF3 alleviates ischemic stroke and inhibits ferroptosis via activating the Keap1/Nrf2/HO-1 pathway, which provides theoretical supports for ischemic stroke.

关键词： IDD   NP cells   ScRNA-seq   Ferroptosis   Atf3   Rps6+/Cxcl1  

摘要： ObjectiveRecently, several studies have reported that nucleus pulposus (NP) cell ferroptosis plays a key role in IDD. However, the characteristics and molecular mechanisms of cell subsets involved remain unclear. We aimed to define the key factors driving ferroptosis, and the characteristics of ferroptotic NP cells subsets during *** accumulation of iron ions in NP tissues of rats caudal intervertebral discs (IVDs) was determined by Prussian blue staining. Fluorescent probe Undecanoyl Boron Dipyrromethene (C11-BODIPY) and lipid peroxidation product 4-Hydroxynonenal (4-HNE) staining were performed to assess lipid peroxidation level of NP cells. The differentially expressed genes in NP tissues with aging were overlapped with FerrDB database to screen ferroptosis driving genes associated with aging-related IDD. In addition, single cell sequencing (ScRNA-seq) was used to map the NP cells, and further identify ferroptotic NP cell subsets, as well as their crucial drivers. Finally, cluster analysis was performed to identify the marker genes of ferroptotic NP *** staining showed that, compared with 10 months old (10M-old) group, the accumulation of iron ions increased in NP tissues of 20 months old (20M-old) rats, and the level of lipid peroxidation was also enhanced. 15 ferroptosis driving factors related to IDD were selected by cross-enrichment. ScRNA-seq identified 14 subsets in NP tissue cells, among which the number and ratio of 5 subsets was reduced, and the intracellular ferroptosis related signaling pathways were significantly enriched, accompanied by enhanced cell lipid peroxidation. Notably, ranking the up-regulation fold of ferroptosis related genes, we found Atf3 was always present within TOP2 of these five cell subsets, suggests it is the key driving factor in NP cell ferroptosis. Finally, cluster cross-enrichment and fluorescence colocalization analysis revealed that Rps6 +/Cxcl1- was a common molecular feature among the 5 fer

关键词： ATF3   CCDC86   ERK/MAPK signaling   Glioma   Glycolysis  

摘要： Glioma, an aggressively malignant brain tumor with a poor prognosis, comprises nearly 50% of all primary malignant brain tumors. Despite its significance in other cancers, the role of coiled-coil domain containing 86(CCDC86) in glioma remains largely unexplored. Our study revealed a significant up-regulation of CCDC86 expression in glioma tissues, correlating notably with patient age, tumor recurrence, and pathological grade. Moreover, elevated CCDC86 level was associated with a worsened prognosis among glioma patients. Functional assays demonstrated that CCDC86 knockdown attenuated glioma cell proliferation and migration while inducing apoptosis and cell cycle arrest in vitro and inhibited tumorigenesis in vivo . Furthermore, ATF3 emerged as a downstream target gene of CCDC86, as its knockdown could counteract the oncogenic effects induced by CCDC86 overexpression in glioma cells. Mechanistically, CCDC86 promoted the transcriptional regulation of ATF3 by BHLHE40 through interaction with it, stabilizing the expression of ATF3. Additionally, our investigation unveiled a potential mechanism whereby CCDC86 activated the ERK signaling pathway through ATF3, thus influencing glycolysis to drive tumor progression. In conclusion, our study highlights the pivotal role of CCDC86 in glioma progression, suggesting its potential as a therapeutic target for the development of novel glioma treatments.

关键词： Heart  

摘要： Oxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, ATF3. Genetic ablation of Atf3 in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of ATF3 in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.