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PubMed2025

The Salmonella pathogenicity island 1-encoded small RNA InvR mediates post-transcriptional feedback control of the activator HilA in Salmonella.

UNLABELLED: Salmonella Pathogenicity Island 1 (SPI1) encodes a Type-3 secretion system (T3SS) essential for Salmonella invasion of intestinal epithelial cells. Many environmental and regulatory signals control SPI1 gene expression, but in most cases, the molecular mechanisms remain unclear. Many regulatory signals control SPI1 at a post-transcriptional level, and we have identified a number of small RNAs (sRNAs) that control the SPI1 regulatory circuit. The transcriptional regulator HilA activates the expression of the genes encoding the SPI1 T3SS structural and primary effector proteins. Transcription of hilA is controlled by the AraC-like proteins HilD, HilC, and RtsA. The hilA mRNA 5' untranslated region (UTR) is ~350 nucleotides in length and binds the RNA chaperone Hfq, suggesting it is a likely target for sRNA-mediated regulation. We used rGRIL-seq (reverse global sRNA target identification by ligation and sequencing) to identify sRNAs that bind to the hilA 5' UTR. The rGRIL-seq data, along with genetic analyses, demonstrate the SPI1-encoded sRNA invasion gene-associated RNA (InvR) base pairs at a site overlapping the hilA ribosome binding site. HilD and HilC activate both invR and hilA. InvR, in turn, negatively regulates the translation of the hilA mRNA. Thus, the SPI1-encoded sRNA InvR acts as a negative feedback regulator of SPI1 expression. Our results suggest that InvR acts to fine-tune SPI1 expression and prevents overactivation of hilA expression, highlighting the complexity of sRNA regulatory inputs controlling SPI1 and Salmonella virulence. IMPORTANCE: Salmonella Typhimurium infections pose a significant public health concern, leading to illnesses that range from mild gastroenteritis to severe systemic infection. Infection requires a complex apparatus that the bacterium uses to invade the intestinal epithelium. Understanding how Salmonella regulates this system is essential for addressing these infections effectively. Here, we show that the small RNA (sRNA) InvR imposes a negative feedback regulation on the expression of the invasion system. This work underscores the role of sRNAs in Salmonella's complex regulatory network, offering new insights into how these molecules contribute to bacterial adaptation and pathogenesis.

Genomic Islands↗

PubMed2026

PTBP1 at the host-virus interface: mechanistic roles in viral RNA translation, replication, and immune modulation.

Viruses require the involvement of host RNA binding proteins for completion of important steps of their life cycle. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA-binding protein found ubiquitously which performs important regulatory functions like alternative splicing, RNA stability, RNA localization, and translation by virtue of its four RRMs and shuttling between nucleus and cytoplasm. There is increasing evidence showing that many viruses make use of such regulatory roles of PTBP1 to facilitate their gene expression and replication. This review describes the existing mechanistic knowledge about the PTBP1 functions during viral infection, paying attention to the role of PTBP1 in viral RNA translation, viral RNA genome replication, and regulation of host antiviral response. Special attention is paid to the regulation by PTBP1 of IRES-dependent translation of enteroviruses and hepatitis C virus, as well as to the PTBP1 contribution to RNA stabilization, long-distance RNA interactions, and genome cyclization of flaviviruses such as dengue virus and Japanese encephalitis virus. Recent data on the PTBP1 function in coronavirus RNA metabolism are discussed as well. Furthermore, the role of PTBP1 in being both proviral and antiviral is reviewed in terms of innate immunity signalling pathways, stress granule biology, and virus-host interaction. Finally, we will explore the possibility of PTBP1 being used as a host-directed antiviral drug target despite the hurdles in doing so considering its multifunctionality as an essential cellular RNA-binding protein.

Polypyrimidine Tract-Binding Protein↗

PubMed2024

CLN3 transcript complexity revealed by long-read RNA sequencing analysis.

BACKGROUND: Batten disease is a group of rare inherited neurodegenerative diseases. Juvenile CLN3 disease is the most prevalent type, and the most common pathogenic variant shared by most patients is the "1-kb" deletion which removes two internal coding exons (7 and 8) in CLN3. Previously, we identified two transcripts in patient fibroblasts homozygous for the 1-kb deletion: the 'major' and 'minor' transcripts. To understand the full variety of disease transcripts and their role in disease pathogenesis, it is necessary to first investigate CLN3 transcription in "healthy" samples without juvenile CLN3 disease. METHODS: We leveraged PacBio long-read RNA sequencing datasets from ENCODE to investigate the full range of CLN3 transcripts across various tissues and cell types in human control samples. Then we sought to validate their existence using data from different sources. RESULTS: We found that a readthrough gene affects the quantification and annotation of CLN3. After taking this into account, we detected over 100 novel CLN3 transcripts, with no dominantly expressed CLN3 transcript. The most abundant transcript has median usage of 42.9%. Surprisingly, the known disease-associated 'major' transcripts are detected. Together, they have median usage of 1.5% across 22 samples. Furthermore, we identified 48 CLN3 ORFs, of which 26 are novel. The predominant ORF that encodes the canonical CLN3 protein isoform has median usage of 66.7%, meaning around one-third of CLN3 transcripts encode protein isoforms with different stretches of amino acids. The same ORFs could be found with alternative UTRs. Moreover, we were able to validate the translational potential of certain transcripts using public mass spectrometry data. CONCLUSION: Overall, these findings provide valuable insights into the complexity of CLN3 transcription, highlighting the importance of studying both canonical and non-canonical CLN3 protein isoforms as well as the regulatory role of UTRs to fully comprehend the regulation and function(s) of CLN3. This knowledge is essential for investigating the impact of the 1-kb deletion and rare pathogenic variants on CLN3 transcription and disease pathogenesis.

Humans↗

PubMed2025

Discrete Subdomains Establish Epigenetic Diversity in Subtelomeric Heterochromatin.

Subtelomeres are imperfect repeats adjacent to telomeres that are repressed by heterochromatin. Although essential for genome integrity, their repetitive nature has thwarted dissection of local heterochromatin assembly and maintenance mechanisms. Here, we engineered Schizosaccharomyces pombe strains carrying fluorescent reporters at a single subtelomere. We find that subtelomeric heterochromatin is organized into discrete subdomains that nucleate at telomere-proximal and cryptic internal sites. Telomere-proximal regions depend on canonical shelterin or RNA interference nucleation pathways, while telomere-distal regions require nucleosome remodelers, histone chaperones, and boundary-associated factors. Using multi-generational live imaging and targeted perturbations, we show that subtelomeric subdomains display position-specific, clonally variable silencing across a spectrum of robust to fragile epigenetic states. This clonal variegation is also induced by naturally occurring subtelomeric structural variants. These findings demonstrate that subtelomeric heterochromatin maintenance is not uniform but rather governed by local chromatin context and architecture.

H3K9 methylation↗

PubMed2026

Maintenance of nucleosome organization through replication and transcription counteracts aberrant coalescence of active chromatin.

Nucleosomes with their associated modifications organize and regulate the genome. It is unclear how this is integrated with the requirement of replication and transcription to access the DNA template without jeopardizing chromatin function. Here, we reveal a unified requirement for the histone chaperone FACT in mediating nucleosome disruption and reassembly during mammalian replication and transcription. Upon acute FACT depletion, replisome and RNA polymerase progression is halted genome wide, and chromatin structure in their wake collapses, with reduced nucleosome occupancy, irregular spacing, and intermediate assemblies. Chromatin states deteriorate as modified histones are lost due to a lack of histone recycling. Chromatin fiber disorder further manifests in the 3D genome, triggering active genes to coalesce in aberrant microcompartments. Similarly, aberrant compartments form in cells failing to maintain chromatin fiber structure through replication. Nucleosome organization therefore dynamically regulates genome architecture, guarding against spurious chromatin aggregation.

Nucleosomes↗

PubMed2026

Dynamic evolution of chaperone-mediated autophagy is associated with tumor microenvironment remodeling and prognostic stratification in lung adenocarcinoma: insights from single-cell transcriptomics, ensemble machine learning, and experimental validation.

BACKGROUND: Lung adenocarcinoma (LUAD) shows prognostic heterogeneity, and tumor-node-metastasis (TNM) staging is limited for individualized management. Chaperone-mediated autophagy (CMA) maintains proteostasis, but its role during adenocarcinoma in situ (AIS)-minimally invasive adenocarcinoma (MIA)-invasive adenocarcinoma (IAC) progression remains unclear. METHODS: Single-cell RNA sequencing (scRNA-seq) data from GSE189357 and bulk transcriptomes from The Cancer Genome Atlas (TCGA)-LUAD and Gene Expression Omnibus (GEO) cohorts were integrated. CMA activity, cell-cell communication, weighted gene co-expression network analysis (WGCNA), tumor-normal differential expression, machine-learning survival modeling, tumor microenvironment (TME) features, drug sensitivity, and EPC1 function were analyzed. RESULTS: CMA-high tumor epithelial cells increased from AIS (58.1%) to MIA (65.7%) but declined in IAC (44.4%; p < 0.001). CMA-low cells preferentially received fibroblast-derived extracellular matrix cues. A CMA-negatively correlated module identified 69 core genes. Random survival forest (RSF) performed best among 117 machine-learning combinations (mean concordance index > 0.873). High-risk patients had worse survival across cohorts, and the risk score was independently associated with overall survival (hazard ratio = 16.013, 95% confidence interval: 9.579-26.768, p < 0.001). High-risk tumors showed proliferative activation and M0 macrophage enrichment, whereas low-risk tumors showed stronger immune-related signaling. EPC1 overexpression suppressed malignant phenotypes in A549 cells. CONCLUSION: CMA dynamics are associated with stromal and immune remodeling during LUAD progression. A CMA-based model provides robust prognostic stratification and may offer a basis for future TME-guided studies.

Chaperone-mediated autophagy↗

PubMed2026

Emergent 3D genome reorganization and graded gene control from the stepwise assembly of transcriptional condensates.

Transcriptional condensates are clusters of transcription factors, coactivators, and RNA Pol II associated with gene activation, yet how they assemble and function within the cell remains unclear. Here, we show that transcriptional condensates form in a stepwise manner to enable both graded and three-dimensional (3D) gene control in the yeast heat shock response (HSR). First, the transcription factor Hsf1 (heat shock factor 1) clusters upon partial dissociation from the chaperone Hsp70. Next, the coactivator Mediator partitions following further Hsp70 dissociation and Hsf1 phosphorylation. Finally, Pol II condenses, driving emergent coalescence of HSR genes. Separation-of-function Hsf1 mutants revealed graded (non-switch-like) control of transcription and a decoupling of condensate formation and gene activation. Fully assembled HSR condensates promoted adaptive 3D genome reconfiguration, suggesting a role beyond transcription. In the HSR, differential condensation of the transcriptional machinery quantitatively tunes gene expression and qualitatively remodels the 3D genome.

3D genome↗

PubMed2026

Hepatitis C Virus Enhances Lysosome-Associated Membrane Protein 2 A Transcription Through Nuclear Factor Erythroid 2-Related Factor 2 to Support Viral Replication.

Hepatitis C virus (HCV) establishes persistent infection by rewiring host stress-response pathways. Chaperone-mediated autophagy (CMA) contributes to HCV replication, but it remains unclear whether HCV regulates lysosome-associated membrane protein 2 A (LAMP-2A), the rate-limiting receptor for CMA. Here, we examined LAMP-2A regulation in HCV-infected Huh-7.5 cells. HCV infection increased LAMP-2A promoter activity, mRNA, and protein abundance, indicating transcriptional upregulation. Among candidate stress-responsive transcription factors, nuclear factor erythroid 2-related factor 2 (NRF2), hypoxia-inducible factor 1α (HIF-1α), and nuclear factor of activated T cells 1 (NFAT1) were elevated in infected cells. However, promoter mutagenesis identified NRF2 as the principal direct regulator. Mutation of the NRF2-responsive antioxidant response element markedly reduced basal and HCV-induced LAMP-2A promoter activity. Chromatin immunoprecipitation assays revealed NRF2 association with the LAMP-2A promoter, and HCV infection increased nuclear accumulation and Ser40 phosphorylation of NRF2. Functionally, shRNA-mediated knockdown of LAMP-2A reduced intracellular HCV RNA and protein levels. These findings identify an NRF2-LAMP-2A regulatory axis engaged during HCV infection and support a model in which HCV upregulates LAMP-2A to establish a cellular environment favorable for viral replication.

Hepacivirus↗

PubMed2026

Transcriptomic insights into thermal stress reveal physiological trade-off between thermal stress adaptation and reproductive investment in Spodoptera litura.

Spodoptera litura, a highly polyphagous lepidopteran pest, poses a major threat to agricultural productivity due to its remarkable adaptability to diverse environmental conditions. Although heat stress is known to trigger transcriptional reprogramming in insects, the molecular mechanisms underlying thermal stress responses in S. litura remain poorly understood. In the present study, fourth-instar larvae were exposed to acute heat stress (44 °C) and compared with control conditions (27 ± 1 °C) to investigate heat-induced transcriptional alterations affecting physiology and reproduction. High-quality RNA-Seq data achieved more than 80% mapping efficiency, with a total of 15,782 transcripts were identified. Transcriptome analysis of S. litura larvae showed 323 differentially expressed genes (DEGs), of which 262 genes were significantly upregulated and 61 were downregulated in heat-stressed larvae compared to the control group. The DEGs were associated with stress response, reproduction, signalling, proteostasis, detoxification, oxidative stress, metabolism, development, and chromatin regulation. Heat shock proteins genes, including HSP70, HSP90, and HSP27, together with co-chaperones such as TRET-1, STIP1, and Starvin, were strongly upregulated, indicating enhanced cellular protection against protein damage and oxidative stress under heat stress. Conversely, key reproductive and cell cycle-related genes, including BARR, CAPD2, FEO, CDK2 and MORULA, were significantly downregulated, suggesting reproductive impairment and developmental arrest. RT-qPCR validation corroborated the RNA-Seq findings, demonstrating a heat-induced physiological trade-off that prioritizes survival over reproduction. Consistent with these molecular responses, heat-stressed insects exhibited marked reproductive impairment, including significant reductions in gonadosomatic index, eupyrene sperm bundle count, mating frequency, mating success, female calling behaviour, copulation duration, fecundity, and egg fertility. Collectively, these findings provide comprehensive insights into the molecular basis of thermal adaptation in S. litura and demonstrate that acute heat stress compromises reproductive fitness while activating conserved stress-response pathways that promote short-term survival.

Animals↗

PubMed2026

An ATP-Driven N Protein-DDX21 Molecular Switch Dynamically Controls SARS-CoV-2 RNA G-Quadruplex Heterogeneity.

The SARS-CoV-2 RNA genome functions as a highly structured regulatory scaffold. Although bioinformatic analyses predict widespread RNA G-quadruplexes (G4s) across the viral genome, their structural diversity and regulatory mechanisms remain poorly understood. Here, we report a diverse landscape of viral G4s encompassing parallel and non-canonical topologies with remarkable thermostability. Unlike typical eukaryotic G4s, these two-tetrad viral G4s exhibit a hierarchical ion-dependent mechanism, in which K+ establishes the core fold, and Mg2 + acts as a secondary regulator promoting conformational compaction. Single-molecule FRET analysis further distinguishes rigid, long-lived G4 folds from highly dynamic, metastable species, defining a continuum of conformational states along the viral genome. Functionally, we identify a synergistic yet competitive interplay between the viral nucleocapsid (N) protein and host helicase DDX21. While the N protein acts as a molecular chaperone to promote G4 folding, DDX21 selectively resolves these structures in an ATP-dependent manner. Strikingly, N and DDX21 jointly constitute a finely tuned, ATP-driven molecular switch, where ATP availability dictates the equilibrium between G4-stabilized and resolved states. Our findings establish a mechanistic framework for the active regulation of SARS-CoV-2 RNA architecture and reveal a multilayered host-virus regulatory axis that modulates viral genome heterogeneity.

DEAD‐box helicases↗

PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗

PubMed2026

Regulation of the histone H3K36 methyltransferase Set2 by the histone chaperone Spt6.

Histone H3 lysine 36 methylation is a conserved histone modification that is critical for maintaining eukaryotic transcriptional fidelity and genomic stability. In Saccharomyces cerevisiae, this modification is catalyzed by Set2, an ortholog of the mammalian H3K36 methyltransferase SETD2. Previous genetic, biochemical, and structural studies showed that Set2 activity is repressed by a Set2 autoinhibitory domain (AID) and that activation requires the direct binding of the histone chaperone Spt6. To study the role of Spt6 and Set2 autoinhibition in vivo, we have isolated and analyzed multiple classes of Spt6 and Set2 mutants. Our results suggest an autoinhibited form of Set2 in which the catalytic domain (CD) is bound by the AID. In strong agreement with our genetic results, biophysical experiments demonstrate that the CD and AID physically interact, and that the autoinhibition mutants disrupt this interaction. Finally, RNA sequencing and chromatin immunoprecipitation and sequencing studies show the importance of the Set2-Spt6 interaction for transcription and H3K36 methylation genome-wide. Taken together, our results support a model in which Set2 exists in an inactive, autoinhibited state in vivo through direct CD-AID interactions, with binding by Spt6 required to release the autoinhibition.

Saccharomyces cerevisiae Proteins↗

PubMed2025

A long noncoding RNA with enhancer-like function in pig zygotic genome activation.

The zygotic genome activation (ZGA) is crucial for the development of pre-implantation embryos. Long noncoding RNAs (lncRNAs) play significant roles in many biological processes, but the study on their role in the early embryonic development of pigs is limited. In this study, we identify lncFKBPL as an enhancer-type lncRNA essential for pig embryo development. lncFKBPL is expressed from the 4-cell stage to the morula stage in pig embryos, and interference with lncFKBPL leads to a developmental arrest at the 8-cell stage. Mechanistic investigations uncover that lncFKBPL is able to bind to MED8, thereby mediating enhancer activity and regulating FKBPL expression. Additionally, FKBPL interacts with the molecular chaperone protein HSP90AA1, stabilizing CDK9 and boosting its protein-level expression. Elevated CDK9 levels enhance Pol II phosphorylation, facilitating ZGA. Our findings illuminate the role of lncFKBPL as an enhancer lncRNA in pig ZGA regulation and early embryo development, providing a foundation for further exploration in this area.

Animals↗

PubMed2026

Regulation of the histone H3K36 methyltransferase Set2 by the histone chaperone Spt6.

Histone H3 lysine 36 methylation is a conserved histone modification that is critical for maintaining eukaryotic transcriptional fidelity and genomic stability. In Saccharomyces cerevisiae, this modification is catalyzed by Set2, an ortholog of the mammalian H3K36 methyltransferase SETD2. Previous genetic, biochemical, and structural studies showed that Set2 activity is repressed by a Set2 autoinhibitory domain (AID) and that activation requires the direct binding of the histone chaperone Spt6. To study the role of Spt6 and Set2 autoinhibition in vivo, we have isolated and analyzed multiple classes of Spt6 and Set2 mutants. Our results suggest an autoinhibited form of Set2 in which the catalytic domain is bound by the AID. In strong agreement with our genetic results, biophysical experiments demonstrate that the catalytic domain and AID physically interact, and that the autoinhibition mutants disrupt this interaction. Finally, RNA-seq and ChIP-seq studies show the importance of the Set2-Spt6 interaction for transcription and H3K36 methylation genome-wide. Taken together, our results support a model in which Set2 exists in an inactive, autoinhibited state in vivo through direct catalytic domain-AID interactions, with binding by Spt6 required to release this autoinhibited state.

Journal Article↗

PubMed2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans↗

PubMed2026

Comparative Transcriptomics Reveals Shared Downstream Pathways in Craniofacial Pathology.

Treacher Collins syndrome and Nager syndrome are craniofacial developmental disorders caused by defects in ribosome biogenesis and RNA splicing, respectively, yet they exhibit overlapping abnormalities affecting neural crest cell-derived craniofacial structures. To investigate shared downstream pathogenic mechanisms, we performed a comparative transcriptomic analysis of zebrafish polr1c and sf3b4 mutant models from our previous studies. Comparative analysis identified 17 shared differentially expressed genes (DEGs) between polr1c and sf3b4 mutants, with the majority of shared genes dysregulated in the same direction, indicating a coordinated rather than random transcriptional response. Gene ontology analysis identified ATP-dependent protein folding chaperone activity as the only shared molecular function, driven in part by upregulation of hsp90aa1.2, indicating a common proteostasis response. Because chaperone activity is linked to extracellular matrix (ECM) protein processing, we cross-referenced DEGs from both mutants against the curated zebrafish matrisome. Three of the 17 shared DEGs (serpinh1b, il11a, and lepa) were matrisome-associated and upregulated in both mutants. Serpinh1b, a collagen-specific chaperone, was strongly expressed in craniofacial cartilage and mesenchymal populations during pharyngeal arch development and exhibited nearly identical fold changes in both mutants. Il11a is of particular interest because its receptor, IL11RA, is known to be associated with human craniosynostosis, suggesting potential relevance to craniofacial development. Together, it is possible to hypothesize that shared chaperone-associated transcriptional changes, together with altered ECM-related gene expression, may contribute to polr1c- and sf3b4-associated craniofacial disorders, warranting further functional validation.

Extracellular Matrix↗

PubMed2026

Transcriptomic and Proteomic Insights into Mucosal Immune Responses of Asian Seabass (Lates calcarifer) After Sequential Mucosal Vaccination Against Bacterial Pathogens.

Bacterial diseases caused by Flavobacterium covae (Fc), Vibrio harveyi (Vh), Vibrio vulnificus (Vv) and Photobacterium damselae (Pd) seriously constrain Asian seabass aquaculture. Here we dissect the mucosal immune mechanisms engaged by a five-month sequential vaccination strategy that combines nanoemulsion immersion priming with multivalent oral hydrogel boosting. Juvenile seabass were vaccinated, then challenged with F. covae by freshwater immersion and with a Vibrio-Photobacterium (Vh/Vv/Pd) mix by immersion or intraperitoneal injection. Gills were sampled after immersion challenges and intestine after injection, and profiled by RNA sequencing and label-free quantitative proteomics, with selected genes validated by RT-qPCR. Principal component analysis showed clear separation of vaccinated and control fish in all tissues and challenges, indicating a strong and coherent transcriptional reprogramming. Vaccination markedly increased the number of upregulated genes, with Gene Ontology enrichment revealing dominant signatures of ribosome biogenesis, RNA processing, lysosomal organization and immune response. KEGG analysis highlighted cytokine receptor interaction; NOD and Toll-like receptor signaling; oxidative phosphorylation; and phagosome, lysosome and cell adhesion molecule pathways, consistent with heightened antimicrobial readiness. Volcano plots and focused heatmaps showed strong induction of interferon-stimulated genes, cytokines and chemokine receptors, complement components, macrophage mannose receptor, epithelial barrier mediators and numerous immunoglobulin transcripts, with tissue- and challenge-specific patterns. Proteomics corroborated these trends, demonstrating a higher abundance of immunoglobulin heavy chains, complement proteins, cathepsins, heat shock and redox chaperones, ribosomal proteins and cytoskeletal and adhesion regulators in vaccinated mucosae. Integrated pathway mapping linked endothelial adhesion molecules and leukocyte integrins with T cell costimulation networks and an intestinal immune network for immunoglobulin production, including enhanced pIgR-mediated transcytosis. Overall, the sequential vaccination regimen was associated with coordinated transcriptomic and proteomic signatures related to epithelial responses, innate immunity, and humoral immune functions across gill and intestinal tissues. These molecular patterns were accompanied by improved survival following bacterial challenge; however, the present data do not directly demonstrate the functional activity of the inferred immune mechanisms in Asian seabass.

Animals↗

PubMed2026

An integrated proteomics and transcriptomics analysis highlights concordance between protein turnover and carbohydrate transport and metabolism as key functional categories during the growth of Trichophyton rubrum.

Dermatophytes are a class of keratinophilic skin fungi that invade host skin, hair, and nails to acquire nutrients. An integrated multi-omics approach utilizing liquid chromatography-tandem mass spectrometry and RNA-seq after growth in a protein-rich soy medium was employed to capture the major subset of secreted protein families of Trichophyton rubrum. The secretome consisted mainly of proteases and cell wall-degrading enzymes, with subtilisins (Sub6 and Sub7), metallopeptidase (LAP2), and chitinase having the most abundant peptides. Transcriptional profiling indicated fungal adaptation in protein-rich media to process the protein nutrients through modulation of metabolism and general cellular function pathways. Correlation analysis between proteomics and transcriptomics data using functional KOG categories shows high concordance of KOG categories O (posttranslational modification, protein turnover, and chaperones), P (inorganic ion transport and metabolism), and G (carbohydrate transport and metabolism), as per cosine similarity analysis.IMPORTANCEDermatophytes are keratinophilic skin fungal pathogens that invade host skin, hair, and nails to acquire nutrients. There is an epidemic-like increase in infections, as well as an increase in antimicrobial resistance among dermatophytes, as witnessed over the last decade. There is hence a need to understand the key pathways and virulence factors required during growth and infection. We present an integrated multi-omics analysis (proteomics and transcriptomics data) using a vector-based similarity approach to show high concordance of KOG functional categories belonging to posttranslational modification, protein turnover, carbohydrate transport, and metabolism.

Proteomics↗