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7 recordsLinked to original sources
PubMed2025

Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response.

Cells rapidly and extensively remodel their transcriptome in response to stress to restore homeostasis, but the underlying mechanisms are not fully understood. Here, we characterize the dynamic changes in transcriptome, epigenetics, and 3D genome organization during the integrated stress response (ISR). ISR induction triggers widespread transcriptional changes within 6 h, coinciding with increased binding of ATF4, a key transcriptional effector. Notably, ATF4 binds to hundreds of genes even under non-stress conditions, priming them for stronger activation upon stress. The transcriptional changes at ATF4-bound sites during ISR do not rely on increased H3K27 acetylation, chromatin accessibility, or rewired enhancer-promoter looping. Instead, ATF4-mediated gene activation is linked to the redistribution of CEBPγ from non-ATF4 sites to a subset of ATF4-bound regions, likely by forming an ATF4/CEBPγ heterodimer. CEBPγ preferentially targets the sites pre-occupied by ATF4, as well as genomic regions exhibiting a unique higher-order chromatin structure signature. Thus, the transcriptional responses during ISR are largely pre-wired by intrinsic chromatin properties. These findings provide critical insights into transcriptional remodeling during ISR with broader implications for other stress responses.

Activating Transcription Factor 4↗
PubMed2026

ATF4-histone 2-hydroxyisobutyrylation feedback loop drives sepsis-induced inflammation.

BACKGROUND AND PURPOSE: The role and mechanisms of lysine 2-hydroxyisobutyrylation (Khib) in the acute inflammatory phase of sepsis remain unclear. We investigated the function and underlying mechanisms of histone H4 lysine 5 2-hydroxyisobutyrylation (H4K5-hib) in sepsis-induced inflammation in vivo and in vitro. EXPERIMENTAL APPROACH: Acute sepsis was induced by caecal ligation and puncture (CLP) in mice, and inflammatory responses were modelled in lipopolysaccharide (LPS)-stimulated macrophages. CUT&Tag-seq was used to identify genomic targets associated with H4K5-hib and activating transcription factor 4 (ATF4). Immunofluorescence, Western blotting, qPCR, dual-luciferase assays, and ELISA were performed to investigate the underlying mechanisms. KEY RESULTS: H4K5-hib levels were increased in macrophages during the acute inflammatory phase of sepsis. LPS stimulation enhanced H4K5-hib enrichment at the ATF4 promoter, thereby promoting ATF4 transcription. Inhibition of EP300-mediated 2-hydroxyisobutyrylation or mutation of H4K5 abolished ATF4 activation. Increased H4K5-hib activated the ATF4/NLRP3 signalling axis, promoting inflammasome assembly and amplifying inflammatory responses. ATF4 directly bound to the EP300 promoter and enhanced its transcription, forming a positive feedback loop that further increased H4K5-hib levels. In CLP-induced sepsis, pharmacological inhibition of EP300 or ATF4 reduced H4K5-hib levels and suppressed NLRP3 inflammasome activation. CONCLUSION AND IMPLICATIONS: These findings reveal a previously unrecognized epigenetic mechanism underlying sepsis-induced inflammation and identify the EP300/ATF4/H4K5-hib positive feedback loop as a potential therapeutic target for sepsis.

Animals↗
PubMed2025

MLL1 downregulation drives hair cell ferroptosis via mitochondrial and endoplasmic reticulum stress mechanisms through PERK-eIF2α-ATF4-Chop and PI3K/Akt-Lrp1 signaling pathway.

BACKGROUND: Sensorineural hearing loss is characterized by irreversible hair cell (HC) degeneration. Ferroptosis, which is marked by the accumulation of reactive oxygen species and elevated levels of lipid peroxidation products, has been shown to contribute to drug-mediated auditory impairment. This study aimed to elucidate the role of mixed-lineage leukemia 1 (MLL1) in HC survival in the auditory system. METHODS: The HEI-OC1 auditory cell line and postnatal cochlear explants were evaluated using MM-102, a specific MLL1 histone methyltransferase inhibitor. Western blotting, quantitative polymerase chain reaction, electron microscopy, and immunofluorescence were used to elucidate the role of MLL1 in regulating ferroptosis in HC injury. RNA sequencing (RNA-seq) was used to analyze the molecular mechanisms of MLL1 intervention in HC injury from an epigenetic perspective. RESULTS: Our findings demonstrated that immunofluorescence staining revealed a crucial role of MM-102 in promoting intracellular accumulation of lipid peroxides and ferrous ions. Subsequent analysis showed MLL1 downregulation-induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, with transmission electron microscopy imaging confirming ultrastructural alterations in mitochondria and ER. Mechanistic investigations identified the PERK-eIF2α-ATF4-Chop signaling axis as the regulatory pathway, evidenced by Western blotting quantification of phosphorylated PERK (p-PERK), ATF4, and Chop levels. RNA-seq analysis revealed 741 differentially expressed genes (335 upregulated and 406 downregulated). Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis specifically highlighted significant enrichment of the PI3K/Akt-Lrp1 pathway, with corresponding activation patterns of phospho (p)-Akt and Lrp1 confirmed through Western blotting analysis. CONCLUSIONS: MLL1 downregulation initiates ferroptosis in cochlear HCs. This process is intrinsically associated with the activation of mitochondrial dysfunction and ER stress. The study highlights the importance of MLL1 in HC survival, suggesting its potential as a therapeutic target for treating hearing loss.

Endoplasmic Reticulum Stress↗
PubMed2026

MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.

MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of messenger RNA (mRNA). MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Reestablishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Last, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.

Humans↗
PubMed2025

MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma.

MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.

Cell Biology↗
PubMed2026

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

Humans↗
PubMed2025

Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.

Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.

Amyotrophic Lateral Sclerosis↗