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PubMed2025

Transcription factor 4 maintains endothelial cell identity by inhibiting endothelial to mesenchymal transition.

Endothelial to mesenchymal transition (EndoMT) is essential for embryonic heart development and contributes to many pathological processes. It is unclear how the balance between endothelial cell (EC) identity and EndoMT mediators is regulated to drive this transition. This study identifies transcription factor 4 (TCF4; also known as ITF2) as a critical EC identity gene. TCF4 knockdown impairs EC phenotype and function, and induces a transition towards a mesenchymal-like state. This discovery suggests that TCF4 safeguards EC identity against EndoMT. Mechanistically, TCF4 directly binds to the promoter of multiple key genes in the transforming growth factor-β (TGFβ) signaling pathway, thereby repressing their expression. TCF4 expression is consistently down-regulated in three EndoMT models. TCF4 down-regulation diminishes its inhibitory effect on the TGFβ signaling pathway, leading to pathway activation and subsequently enhancing EndoMT. This, in turn, further suppresses TCF4 expression. Consequently, the TCF4-TGFβ feedback loop is formed to intensify the EndoMT process. We demonstrate that introducing exogenous TCF4 disrupts this TCF4-TGFβ feedback loop of EndoMT, rescuing the EC phenotype and function under TGFβ stimulation, as well as ECs from human patients with heart failure. Our results reveal a key role for TCF4 in safeguarding EC identity and preventing EndoMT, suggesting a therapeutic potential of targeting TCF4 for EndoMT-related cardiovascular diseases.

Humans↗

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↗

PubMed2026

Biallelic rescue of CTG18.1 in two Fuchs endothelial corneal dystrophy-derived iPSC lines (SCTCi047-A-2, SCTCi046-A-2) following a two-step gene editing strategy.

Fuchs endothelial corneal dystrophy (FECD) is an age-related condition distinguished by the degeneration of the corneal endothelium. An intronic CTG18.1 repeat in the transcription factor 4 (TCF4) gene has been associated with a 78-fold increased risk of developing the disease when at least one copy of the CTG18.1 expands above 50 repeats. Employing patient-derived material, we applied a dual CRISPR/Cas9-mediated editing approach to rescue the expansion. Combining non-homologous end-joining (NHEJ) and homologous direct repair (HDR) events, we generated two FECD-derived +/+(CTG)8 induced pluripotent stem cell (iPSC) lines, which were then successfully characterized, providing relevant isogenic controls for disease-modelling purposes.

Humans↗

PubMed2026

Identification of Critical Genes Related to Breast Cancer with Brain Metastasis Through Bioinformatics Analysis.

INTRODUCTION: Distant metastasis accounts for the majority of Breast Cancer (BC)-related mortality. The brain is one of the most common regions of metastasis. However, the underlying molecular mechanisms remain uncertain. METHODS: In this study, gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Datasets GSE100534 and GSE52604, containing 16 primary brain tumor samples and 38 breast cancer brain metastasis samples, were used to identify the Differentially Expressed Genes (DEGs). The Metascape database was used to analyze enriched Gene Ontology (GO) entries and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway entries in DEGs. The STRING database was then used to construct a Protein-Protein Interaction (PPI) network, and the Cytoscape platform was employed to visualize the network. Furthermore, the Kaplan-Meier curve was used to analyze the Relapse-Free Survival (RFS) among the hub genes. Finally, the iRegulon plugin was used to construct a regulatory network to find the transcription factors (TFs) that regulate the expression of the hub genes. RESULTS: A total of 344 DEGs, including 182 up-regulated and 162 down-regulated genes, were identified by using the limma package in R. A module with 18 nodes and 9 hub genes was selected from the PPI network by using the plugins MCODE and Cyto- Hubba, respectively. KEGG pathway analysis demonstrated that brain metastasis in BC was closely related to the oocyte cell cycle. The Kaplan-Meier curve showed that high expression of these 9 hub genes was associated with poor RFS in BC patients. TFs' analysis showed that E2F4, SIN3A, FOXM1, and TFDP1 interacted with these hub genes. DISCUSSION: This study revealed that Breast Cancer Brain Metastasis (BCBM) may have a promoting effect on the cell cycle of oocytes and affect the maturation and division of oocytes through the KEGG and GO analyses of 344 DEGs. The selected 9 hub genes (ASPM, BUB1, BUB1B, CCNA2, CCNB1, CDK1, NDC80, NCAPG, and TOP2A) and 4 transcription factors (E2F4, SIN3A, FOXM1, TFDP1) may play a critical role in brain metastasis of BC. CONCLUSION: The results of this study may aid in the early diagnosis and suggest potential targets for the treatment of BCBM.

Brain Neoplasms↗

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↗

PubMed2025

Symbionts with eroded genomes adjust gene expression according to host life-stage and environment.

Symbiotic bacteria in long-term host associations frequently undergo extreme genome reduction. While they retain genes beneficial to the host, their repertoire of transcription factors is severely reduced. Here, we assessed whether genome-eroded symbionts can still regulate gene expression by characterizing the transcriptional responses of obligate symbionts in reed beetles to different temperatures and host life stages. These symbionts feature a small genome (~0.5 Mb), encoding for 9-10 essential amino acid biosynthesis pathways, 0-2 pectinases, and 4-5 transcription factors. We found that the symbionts respond to winter conditions by upregulating a heat-shock sigma factor and downregulating translation machinery. Across life stages, symbionts adjusted gene expression to meet the hosts' nutritional demands, upregulating amino acid biosynthesis in larvae, while expression and activity of host and symbiont enzymes involved in plant cell wall breakdown increased in the folivorous adults. In addition, the regulation of symbiont cell morphology genes corresponded to cell shape differences across life stages. Thus, reed beetle symbionts may use their few transcription factors to respond to the host's environment, highlighting the regulatory potential of long-term coevolved symbionts despite severely reduced genomes.

Symbiosis↗

PubMed2025

Rare variants in MIR184 are a novel genetic cause of Fuchs endothelial corneal dystrophy.

PURPOSE: To identify novel genetic causes of Fuchs endothelial corneal dystrophy (FECD) within a genetically unsolved patient cohort lacking repeat expansions in the TCF4 gene (Exp-). METHODS: A rare variant analysis framework (CoCoRV) was applied to exome data, in combination with in silico modeling, luciferase reporter, and RNA-seq analysis to characterize transcriptome-wide consequences of identified variants. RESULTS: A gene burden analysis identified MIR184, a microRNA encoding gene, to be enriched for rare pathogenic variants within the studied Exp- FECD cohort. In total, 2 noncoding rare variants were identified in 4 unrelated FECD probands: NR_029705.1:n.58G>A and n.73G>T. Both variants altered highly conserved mature sequence residues, were predicted to induce hairpin structural changes, and were experimentally determined to disrupt microRNA-mRNA interactions. RNA-seq of transfected human corneal endothelial cells revealed that the mutants elicited distinct transcriptomic profiles. Enriched KEGG pathways included PI3K-Akt signaling, focal adhesion, and immune response, revealing shared pathogenic mechanisms between MIR184-associated FECD and the more common TCF4 repeat expansion-mediated form of disease. CONCLUSION: MIR184 variants are a novel rare genetic cause of FECD, and common pathways of transcriptomic dysregulation are shared across genetically distinct subtypes of the disease. These pathways may serve as future gene agnostic targets for therapeutic interventions.

Humans↗

PubMed2026

Integrative multi-omics and machine learning identify the SPI1-METTL16-PLIN4 axis as a candidate driver of steatosis in HepG2 cells.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder with limited therapeutic options. This study aimed to identify potential regulators and explore their functional roles in a cellular model of NAFLD. METHODS: WGCNA was performed on the hepatic transcriptomic dataset GSE126848 (31 NAFLD vs. 26 controls), followed by integration with serum proteomic data from 12 NAFLD patients and 12 healthy controls. Hub genes were prioritized using three machine learning algorithms. Functional validation was conducted in a HepG2 cellular steatosis model induced by high fructose (3.2 g/L) and oleic acid (400 μM) for 48 h. Lipid accumulation was assessed by Oil Red O staining and triglyceride/total cholesterol measurement. Inflammation was evaluated by TNF-α and IL-6 secretion (ELISA), and oxidative stress by ROS levels (flow cytometry). The binding interaction between METTL16 and PLIN4 mRNA was validated by RNA immunoprecipitation (RIP)-quantitative PCR. METTL16-mediated m6A modification of PLIN4 was assessed by Methylated RIP (MeRIP)-quantitative PCR. Transcriptional regulation of METTL16 by SPI1 was examined by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS: Integrative analysis identified PLIN4 as a core hub gene. PLIN4 was upregulated in the HepG2 steatosis model (P < 0.001). PLIN4 knockdown alleviated lipid droplet accumulation (P < 0.001), reduced TNF-α and IL-6 secretion (P < 0.01), and decreased ROS levels (P < 0.001) in fructose/oleic acid-treated HepG2 cells. Mechanistically, METTL16 mediated its m6A modification to enhance PLIN4 mRNA stability. Furthermore, SPI1 was found to transcriptionally activate METTL16 by binding to its promoter (P < 0.001). PLIN4 re-expression partially reversed the protective effects of SPI1 knockdown on lipid accumulation (P = 0.01), inflammation (P < 0.05), and oxidative stress (P < 0.001). CONCLUSION: This study identifies the SPI1/METTL16/PLIN4 axis as a potential regulatory mechanism contributing to in vitro steatosis, inflammation, and oxidative stress in steatotic HepG2 cells.

Humans↗

PubMed2026

Decreased expression of Krüppel-like factor 4 is associated with colorectal cancer progression.

Krüppel-like factor 4 (KLF4), a key transcription factor,plays an important role in cell proliferation, differentiation, and apoptosis. Here, we explored the prognostic value of KLF4 and its role in colorectal cancer (CRC) progression. We analyzed transcriptomic data and clinical information related to CRC from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. database. Immunohistochemistry was performed to evaluate KLF4 expression in CRC tissue samples. Additionally, we examined the relationship between clinicopathological factors and patient prognosis using Cox proportional hazards model analysis. Lentiviral transfection was used to create KLF4 knockdown HCT-116 cells. Analysis of the TCGA database and two GEO datasets (GSE21510 and GSE117606) revealed that KLF4 was expressed at low levels in CRC. Furthermore, reduced KLF4 levels correlated with lymph node metastasis, distant metastasis, and advanced TNM staging. ROC curve analysis indicated that KLF4 can effectively differentiate cancerous tissue from normal tissue. Functional enrichment analysis identified KLF4 as significantly linked to the glycoprotein metabolic pathway. Our detection of KLF4 expression in CRC tissue samples confirmed its decreased levels and their association with poorer patient survival. However, KLF4 was not identified as an independent prognostic factor. In vitro, KLF4 knockdown promoted HCT-116 cell migration and invasion and downregulated the mRNA expression of glycoprotein synthesis- and glycosylation-related genes. Conversely, KLF4 re-expression markedly reversed these effects. Our findings suggested that low KLF4 expression served as a predictor factor for disease progression in CRC patients. Furthermore, reduced KLF4 levels enhance the migration and invasion of CRC cells, which may be related to impaired glycoprotein metabolism.

Colorectal cancer↗

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↗

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

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

Early Transcriptional Changes in Neutrophil-Mediated Processes Following Recanalization After Ischemic Stroke.

BACKGROUND: Ischemic stroke is a leading cause of death and long-term disability worldwide. Recanalization therapies, including thrombolysis and mechanical thrombectomy, restore blood flow, yet many patients experience poor outcomes, a phenomenon known as futile recanalization. Given the short therapeutic window for ischemic stroke, identifying early biomarkers to guide targeted interventions and improve outcomes is critical. METHODS: Using a murine middle cerebral occlusion model that mimics a large vessel occlusion with recanalization, a comprehensive microarray analysis from blood samples collected immediately and 3 hours after recanalization (N=44) was performed. Differentially expressed genes, enrichment pathways, immune cell proportions, enriched cell markers, predicted micro-RNAs, and transcription factors were identified using RStudio. Findings in mice were validated with rat middle cerebral artery occlusion (GSE21136) and patients with stroke (GSE16561) data sets to confirm transcriptional changes in peripheral blood postrecanalization. RESULTS: Il1r2, Cd55, Mmp8, Cd14, and Cd69 were early biomarkers poststroke and postrecanalization. Cross-validation revealed Vcan as a differentially expressed gene conserved across species, making it a novel ischemic marker detected as early as 3 hours postrecanalization (4 hours after middle cerebral artery occlusion) in mice, 24 hours after recanalization in rats (middle cerebral artery occlusion-thrombectomy), and within 24 hours from onset in humans receiving recombinant tissue plasminogen activator-thrombolysis. CIBERSORTx and ImmuCellAI-mouse deconvolution showed neutrophil elevation postrecanalization. Leukocyte and neutrophil activation pathways were enriched early after stroke in mice and humans, with stronger upregulation in the female sex. Several regulatory micro-RNAs were identified, and Nuclear Factor Erythroid 4 (NFE4) and Metal Regulatory Transcription Factor 1 (MTF1) emerged as key transcription factors. A coregulatory network underlying neutrophil activity was constructed, highlighting its central role in early responses to ischemia and recanalization, which was enriched in the female sex. CONCLUSIONS: We identified novel early genomic markers for ischemia and recanalization, including the conserved marker Vcan, and highlighted age- and sex-specific immune responses. Mapping a neutrophil-centered coregulatory network provides mechanistic insight into futile recanalization and supports the development of targeted therapies to improve clinical outcomes.

Animals↗

PubMed2025

PqsE adapts the activity of the Pseudomonas aeruginosa quorum-sensing transcription factor RhlR to both autoinducer concentration and promoter sequence identity.

Pseudomonas aeruginosa is an opportunistic human pathogen that poses a significant health threat. Many pathogenic behaviors of P. aeruginosa are under control of the bacterial cell-cell communication system known as quorum sensing (QS). One of the QS master regulators, RhlR, is a receptor/transcription factor that not only relies on binding of its canonical ligand, N-butyrylhomoserine lactone (C4-HSL), but additionally requires a protein-protein interaction with the enzyme, PqsE. We constructed heterologous reporter strains in Escherichia coli that allow measurements of the reliance of RhlR on C4-HSL and/or PqsE binding for the ability to activate transcription of three RhlR-regulated genes: rhlA (PqsE independent), phzM (PqsE dependent), and azeB (PqsE inhibited). Analogous assays measuring activation of the three genes in P. aeruginosa were performed, and the patterns observed correlated tightly with the heterologous reporter assays. These results confirm that the binding of PqsE to RhlR is able to fine-tune RhlR transcription factor activity in a promoter-specific manner and prove that this ability is independent of other factors present in P. aeruginosa.IMPORTANCEPseudomonas aeruginosa is an opportunistic human pathogen that can cause fatal infections. There exists an urgent need for new, effective antimicrobial agents to combat P. aeruginosa. The PqsE-RhlR protein-protein interaction is essential for P. aeruginosa to be able to make toxins, form biofilms, and infect host organisms. In this study, we use both non-native models in Escherichia coli and measurements of gene expression/toxin production in P. aeruginosa to show that the PqsE-RhlR interaction enables fine-tuned gene expression and a heightened ability of P. aeruginosa to adapt to external conditions. These findings will be highly valuable as continued efforts are made to design inhibitors of the PqsE-RhlR interaction and test them as potential antimicrobial agents against P. aeruginosa infections.

Pseudomonas aeruginosa↗

PubMed2026

Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization.

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)-associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

Journal Article↗

PubMed2026

Molecular mechanisms of plant thermal response: from signal transduction and epigenetic regulation to signaling integration.

Global warming intensification elevates heat stress to one of the major threats to crop productivity. This review synthesizes recent advances in understanding the mechanisms governing plant responses to both moderate and acute heat stress, with a focus on the integration of epigenetic regulation and signaling networks that underpin thermal adaptation. This review highlights how transcription factors PHYTOCHROME-INTERACTING FACTOR 4 (PIF4, during thermomorphogenesis) and HEAT SHOCK FACTOR A1s (HSFA1s, in heat shock responses) orchestrate plant adaptive growth through crosstalk among light, circadian, and hormone signaling pathways. Importantly, epigenetic mechanisms, including histone variant H2A.Z dynamics and histone modification reprogramming, function as central regulators of thermal plasticity. Key among these processes are HSFA2-mediated chromatin remodeling and small interfering RNA (siRNA)-dependent control of transgenerational thermomemory. Despite this progress, fundamental questions persist regarding temperature sensing, HSFA1s activation dynamics, and stress signal integration. Multi-omics and synthetic biology approaches are proposed to be pivotal in deciphering conserved principles of plant thermal resilience, ultimately providing a theoretical foundation and molecular breeding strategies for climate-smart crops.

Epigenesis, Genetic↗

PubMed2026

Impact of wheat GRF4-GIF1 morphogenic regulators on transformation and genome editing efficiency in elite barley cultivars.

INTRODUCTION: Efficient genetic transformation is essential for the delivery of the CRISPR/Cas9 genome editing system and thus represents an important technology for breeding-oriented research in barley (Hordeum vulgare L.). However, transformation and plant regeneration from tissue culture remain challenging in non-model barley genotypes. Previous studies demonstrated that expression of a chimeric fusion between two interacting transcription factors, GROWTH-REGULATING FACTOR 4 (GRF4) and GRF-INTERACTING FACTOR 1 (GIF1), enhances regeneration capacity in wheat and other species. METHODS: In this study, we evaluated the effect of the wheat-derived GRF4-GIF1 morphogenic regulators on biolistic transformation and genome editing efficiency in three commercial barley cultivars: Tselinniy 5, Aley, and G-23035. RESULTS: The JD633 construct carrying GRF4-GIF1 enabled recovery of stable transformants in all three genotypes, with efficiencies ranging from 2.5% to 5%, whereas the control construct lacking morphogenic regulators resulted in no transgenic events in any of the tested varieties. Among transformed T0 plantlets, genome editing efficiency reached 64.3%, with predominantly biallelic mutations that were stably inherited in the T1 generation. Molecular screening revealed the presence of plasmid-free edited plants in the T0 generation, likely arising from transient Cas9 expression, and provided evidence of tissue chimerism. DISCUSSION: These results demonstrate that the GRF-GIF system facilitates genome editing, providing a practical framework for accelerating precision breeding in barley.

CRISPR/Cas9↗

PubMed2025

High temperature-responsive DEAR4 condensation confers thermotolerance through recruiting TOPLESS in Arabidopsis nucleus.

Global warming is harmful to plants and threatens crop yields in the world. In contrast to other abiotic stresses, the molecular mechanisms for plant high temperature perception and signaling are still not fully understood. Here, we report that transcription factor DREB AND EAR MOTIF PROTEIN 4 (DEAR4) positively regulates heat tolerance in Arabidopsis thaliana. We further reveal that DEAR4 proteins undergo liquid-liquid phase separation (LLPS) and high temperature could induce DEAR4 condensate formation in the nucleus. Moreover, DEAR4 recruits the transcriptional co-repressor TOPLESS (TPL) into the nuclear speckles under high temperature. The high temperature triggered DEAR4-TPL co-condensates enhance their transcriptional repression activity through modulating histone deacetylation levels of GASA5, which is a reported negative regulator of HEAT SHOCK PROTEINs (HSPs). A genome-wide transcriptional landscape study confirms that DEAR4 induces the expression of multiple HSPs. Taken together, we illustrate a transcriptional repression mechanism mediated by DEAR4 through LLPS to confer plants thermotolerance and open a new avenue for translating this knowledge into crops for improving their heat resistance.

Arabidopsis↗