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PubMed2025

OsIDD6, an INDETERMINATE DOMAIN containing transcription factor in rice, plays an essential role in reproductive development.

INDETERMINATE DOMAIN containing proteins (IDD) are plant-specific transcriptional factors with a diverse range of roles in plants. Among the 15 IDD genes in rice, a staple food crop for the world, only about half have been functionally characterized. To elucidate the function of the remaining members, we created loss-of-function mutants using the CRISPR genome editing technique. Although no mutant exhibited obvious growth phenotypes, the Osidd6 mutant was completely sterile. By genetic crossing, we showed that both the male and female gametophytes were defective in the mutant. Histochemical staining and thin sectioning revealed that microspore development was compromised, likely due to a delay in tapetum degeneration. We also showed that meiosis was impaired in the mutant, resulting in defective megaspore development. Through a series of experiments, including transcriptome analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), in situ hybridization, β-glucuronidase (GUS) staining with promoter-GUS transgenic plants, yeast one-hybrid method, a dual-visible reporter assay, and transcriptional activity assay, we demonstrated that OsIDD6 is expressed in all cell types in the male and female reproductive organs and that the OsIDD6 protein directly regulates genes potentially having a role in meiosis and tapetum development. Since reproductive development is directly related to crop yield, OsIDD6 could be an important target for genetic manipulation in rice breeding.

Oryza↗
PubMed2025

Transposable elements drive evolution and perturb gene expression in Brassica rapa and B. oleracea.

Transposable elements (TEs) significantly influence genomic diversity and gene regulation in plants. Brassica rapa and B. oleracea, with their distinct domestication histories, offer excellent models to explore TE dynamics. Here, we developed a refined TE classification method and systematically analyzed TEs across 12 B. rapa and B. oleracea genomes, identifying 1878 TE families. Approximately half (49.5%) of these TE families were shared between the two species, reflecting a common evolutionary origin, whereas species-specific expansions, particularly among long-terminal repeat (LTR) retrotransposons, underscore their roles in genomic differentiation. We notably characterized a heat-responsive Ty1-copia family (Copia0035) in B. oleracea roots, distinguished by low GC content and the absence of CG and CHG methylation motifs, sharing regulatory similarities with the Arabidopsis heat-induced ONSEN element. Syntenic analyses of gene-TE associations highlighted significant intraspecies TE insertion variability, with more accession-specific insertions in B. rapa and more conserved insertions, often associated with distinct morphotypes in B. oleracea. Gene ontology enrichment indicated TE involvement in developmental, reproductive, and stress response pathways. Transcriptome analysis across diverse accessions revealed that genes proximal to TEs, particularly those regulating floral development and flowering time, exhibit increased expression variability. These findings advance our understanding of TE-mediated genome evolution in Brassica species and underscore their potential utility in breeding and genome engineering strategies for crop improvement.

DNA Transposable Elements↗
PubMed2025

A CRISPR/Cas9 mutant resource for OsSm RNA-binding genes in rice.

Pre-mRNA, produced by eukaryotic DNA transcription, undergoes splicing by the spliceosome, which removes introns and joins exons to form mRNA. The spliceosome is a large and highly dynamic molecular machine. Its core components include five small nuclear ribonucleoproteins (snRNPs) and the various spliceosome-related proteins. The conserved Smith (Sm) complex and the Sm-like proteins (LSm) serve as primary components of the snRNPs. Sm proteins are involved in processes such as pre-mRNA splicing and mRNA degradation, which can regulate gene expression, thereby influencing plant growth, development, and stress responses. While 25 Sm proteins have been identified in rice, their specific roles in regulating rice growth and development remain unclear. In this study, we employed the CRISPR/Cas9 system to edit 15 OsSm genes, and 13 mutants were obtained, with mutation rates ranging from 20.83 to 83.87%. In comparison to the wild type (WT), the mutants exhibited dwarfism, reduced tiller numbers, lower seed-setting rates or sterility, and increased susceptibility to diseases. One Sm mutant, ossmf-2, exhibited dwarfism, delayed flowering, and small grains. Through transcriptome analysis, three target genes, OsMRG702, OsRGG2, and OsLA1, were identified. Mutations of the OsSmF protein may lead to the abnormal splicing of these genes and finally lead to the inhibition of growth and development. Our study first edited the OsSm genes and generated a mutant library in rice. Most of the mutants exhibited abnormal growth and development, underscoring the essential roles of OsSm proteins in rice physiology. Furthermore, this work addresses a critical gap in the functional characterization of Sm proteins in rice. The resulting mutant collection offers valuable germplasm resources and lays a theoretical foundation for elucidating the molecular regulatory networks involving spliceosomal components and their target genes in the control of crop growth, development, and reproduction.

Oryza↗
PubMed2025

Subgenomic divergence and functional innovation following whole-genome duplication in Maleae species of Rosaceae.

Whole-genome duplication (WGD) drives plant evolution by inducing karyotype rearrangements and gene loss through subgenome fractionation. In this study, we investigate post-WGD evolutionary dynamics in Rosaceae, focusing on Maleae species, which uniquely experienced an additional WGD. Using phylogenetic and synteny analyses, we reveal that chromosomal breakpoints act as hotspots for localized fractionation, contributing to blurred homoeologous origins and influencing gene retention patterns. Here, we reconstruct karyotype evolution across Rosaceae subfamilies, highlighting chromosome reductions and lineage-specific rearrangements in Dryadoideae, Rosoideae, and Amygdaloideae. We also identify a bias for retaining transcription factors and hormone-related genes from older WGDs in subsequent polyploidy events. Transcriptome analysis classifies WGD-derived genes in Maleae species, such as apple and loquat, into three expression groups, with hormone-enriched genes playing roles in lignification and fruit-related innovations. These findings demonstrate the interplay between chromosomal breakpoints, biased retention, and functional divergence, revealing their contributions to genomic and phenotypic evolution in Maleae and their adaptive success within Rosaceae.

Genome, Plant↗
PubMed2025

A retrotransposon insertion upstream of Arabidopsis thaliana CRK8 receptor-like kinase modulates a trade-off between pathogen defense and salt tolerance.

In response to necrotrophic fungal pathogens, plants often display quantitative disease resistance (QDR), an immune response with complex genetic determinants. Due to their diversity and small phenotypic effect, the genetic bases of QDR are challenging to characterize. Here, we used genome-wide association mapping in Arabidopsis thaliana natural populations to identify novel determinants of QDR against the fungal pathogen Sclerotinia sclerotiorum. We found that presence-absence polymorphism of the AT4TE56270 Copia transposable element (TE) upstream of the cysteine-rich receptor-like kinase 8 (CRK8) gene is associated with QDR. The presence of the TE associates with higher CRK8 expression in healthy and inoculated plants and increased QDR. The constitutive knockdown of CRK8 reduced QDR, hydrogen peroxide production, and the expression of defense genes upon inoculation. Transcriptome analysis revealed altered defense pathways and salt responses in CRK8 mutants, including impaired glutathione and camalexin biosynthesis, likely contributing to disease susceptibility. Mutants in CRK8 showed altered seed germination on salt, and the absence of AT4TE56270 is associated with enhanced seed germination under salt stress in A. thaliana natural populations. These results reveal a trade-off between salt tolerance and defense against S. sclerotiorum associated with presence-absence polymorphism of a TE.

Arabidopsis↗
PubMed2025

The SlWRKY39-SlZF61 module synergistically regulates SlGSTU42 to enhance low-temperature tolerance in tomato.

Low-temperature stress affects plant growth, and WRKY transcription factors alleviate such damage by regulating downstream genes. This study found that tomato SlWRKY39 significantly responds to low temperatures: its overexpression enhances seedling low-temperature tolerance by promoting ROS scavenging, while knockout exacerbates ROS accumulation and increases sensitivity to low temperatures. Transcriptome analysis indicated induction of glutathione metabolic pathway genes in slwrky39 plants under low-temperature stress. Y1H, EMSA, and Dual-LUC experiments confirmed that SlWRKY39 specifically binds to and activates the SlGSTU42 promoter; silencing SlGSTU42 attenuated the low-temperature tolerance conferred by SlWRKY39 overexpression, verifying that SlWRKY39 improves low-temperature tolerance via direct regulation of SlGSTU42. Additionally, SlZF61 interacts with SlWRKY39, enhancing its regulatory effect on SlGSTU42. SlZF61 overexpression strengthens low-temperature tolerance, while knockout increases sensitivity to low temperatures. In summary, under low-temperature stress, SlWRKY39 and SlZF61 are upregulated expression in tomato; SlWRKY39 binds to the SlGSTU42 promoter, and SlZF61 interacts with SlWRKY39 to form a protein complex, enhancing this binding. They synergistically activate SlGSTU42 transcription, thereby improving seedling low-temperature tolerance by scavenging ROS. This coordinated regulatory mechanism provides a new theoretical basis and practical insights for enhancing tomato low-temperature tolerance and ensuring stable production under low-temperature stress conditions.

Solanum lycopersicum↗
PubMed2026

The transcription factor NO TRANSMITTING TRACT/WIP2 modulates cytokinin homeostasis in Arabidopsis.

The transcription factor WIP2/NO TRANSMITTING TRACT (WIP2/NTT) belongs to the WIP zinc finger family. Loss of WIP/NTT function in Arabidopsis thaliana causes alterations in specific tissues in the gynoecium. It also impairs root development, but only when combined with the loss of WIP4 and WIP5 function, due to redundancy. Certain mutant loss-of-function phenotypes can be recovered by cytokinin application, NTT interacts with cytokinin signaling components, and the phenotypes displayed by plants with increased WIP2/NTT expression also suggest a possible interaction with this pathway. Therefore, the objective of this study was to investigate the relationship between WIP2/NTT and the cytokinin pathway. To overcome the issue of genetic redundancy, we used a commonly used inducible system. We found that WIP2/NTT induction alters cytokinin levels and signaling in a tissue-specific manner, as shown by cytokinin content measurements and TCSn::GFP reporter analysis. Transcriptome analyses revealed candidate target genes related to the cytokinin pathway. Yeast one-hybrid and transactivation assays demonstrated direct NTT binding to regulatory regions of the cytokinin genes ISOPENTENYL TRANSFERASE 5 (IPT5), ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 6 (AHP6), and CYTOKININ OXIDASE/DEHYDROGENASE 7 (CKX7) involved in cytokinin biosynthesis, signaling, and degradation, respectively. Moreover, immunolocalization assays revealed that cytokinin distribution was altered in loss of function mutants and after NTT induction. The results of this work indicate that WIP2/NTT modulates cytokinin homeostasis.

Cytokinins↗
PubMed2026

Moderate expression and activity of flocculins underlie the characteristic flocculation phenotype of Saccharomyces pastorianus.

Flocculation is a key technological trait in lager brewing, governing fermentation performance, yeast recovery, and beer quality. In the allo-aneuploid hybrid yeast Saccharomyces pastorianus, the genetic basis of flocculation remains poorly resolved due to its complex dual sub-genome architecture. Here, we systematically re-annotated and functionally characterized the complete FLO gene repertoire of the Group II strain CBS 1483. Thirteen FLO genes were identified, including allelic variants and a previously uncharacterized adhesin, Flo12, containing a Hyphal_reg_CWP domain instead of the canonical PA14 lectin-binding domain. Structural modeling revealed strong conservation of Ca²+-binding residues in PA14 domains, alongside repeat-region diversification likely contributing to functional variability. Using optogenetic expression in a FLO-null background, we demonstrated that SpcI-FLO9-1 and SpcI-FLO9-2_1 are the strongest drivers of flocculation, exhibiting NewFlo-like sugar sensitivity. Transcriptomic analysis during 17°P wort fermentation showed dynamic induction of these genes coinciding with flocculation onset. Surprisingly, deletion of both loci in CBS 1483 did not abolish but only delayed sedimentation in wort, accompanied by improved maltose utilization and attenuation. These findings reveal functional redundancy and compensatory mechanisms within the FLO network of lager yeast, highlighting the genetic complexity underlying flocculation, and providing a molecular framework to inform yeast selection, strain development, and optimization of the lager fermentation processes.IMPORTANCEFlocculation, the process by which yeast cells aggregate and settle, is essential for producing clear, high-quality lager beer, and for efficient yeast recovery during brewing. However, the genetic basis of this trait in lager yeast has remained poorly understood because these strains possess unusually complex hybrid genomes. In this study, we systematically identified and characterized the complete set of flocculation genes in the industrial lager yeast Saccharomyces pastorianus CBS 1483. We demonstrated that lager yeast flocculation is not controlled by a single dominant gene, but instead emerges from the combined action of several moderately active adhesion proteins that are expressed at low levels during fermentation. Surprisingly, deleting the two strongest candidate genes only delayed, rather than eliminated, sedimentation, revealing a robust compensatory network that preserves brewing performance. These findings refine the current understanding of yeast flocculation and provide a molecular framework for developing brewing strains with improved fermentation efficiency, product consistency, and flavor quality.

Saccharomyces pastorianus↗
PubMed2026

A conserved partner-switching system controls terminal differentiation in multicellular cyanobacteria.

UNLABELLED: Canonical partner-switching systems (PSSs) regulate sigma factor activity through reversible phosphorylation, but their established roles have been largely limited to stress responses and sporulation in Firmicutes. Whether this regulatory mechanism also controls developmental cell fate decisions in other bacterial phyla has remained unknown. Here, we identify a canonical PSS that governs heterocyst differentiation in the multicellular cyanobacterium Anabaena sp. PCC 7120. This system comprises the anti-sigma factor All2284 (NfsS) and the anti-anti-sigma factor All2283 (NfsR). Structural predictions and biochemical assays showed that NfsS phosphorylates NfsR on a conserved serine residue, whereas bacterial two-hybrid and co-purification assays demonstrated that NfsS binds the developmental sigma factors SigC and SigE. Deletion of nfsR abolished heterocyst formation and diazotrophic growth, and transcriptomic analysis revealed broad failure to induce late heterocyst genes, including nitrogen fixation functions such as nifHDK and fdxH. Phylum-wide comparative genomics further showed that PSS genes and putative functional clusters are strongly enriched in filamentous and heterocyst-forming taxa, indicating an association between the expansion of these signaling modules and the emergence of multicellularity and developmental specialization. Together, these findings establish a PSS as a direct regulator of terminal cell differentiation in a gram-negative bacterium and reveal partner switching as a conserved regulatory principle linking environmental signaling to developmental fate in a major bacterial phylum. IMPORTANCE: While partner-switching systems are classically associated with stress responses and sporulation control in Firmicutes, whether this regulatory logic governs developmental decisions in other bacterial phyla has remained unknown. Here, we establish that a related partner-switching mechanism operates in a distinct bacterial lineage, the cyanobacteria, where it controls a major developmental transition involving terminal cell differentiation. Specifically, we show that a phosphorylation-dependent checkpoint involving the anti-sigma factor NfsS and the anti-anti-sigma factor NfsR directly regulates heterocyst formation. Disruption of this switch abolishes cell differentiation and diazotrophic growth, revealing that this system is an obligate gatekeeper for terminal differentiation. Conceptually, these findings substantially extend the known functional repertoire of partner-switching circuits: rather than controlling stress adaptation or spore dormancy, this module has been co-opted to govern a complex, multicellular developmental program in an organism that underpins global carbon and nitrogen cycles. This work, therefore, establishes a new paradigm for phosphorylation-based control of developmental sigma factors and provides a tractable model for dissecting how conserved signaling modules are rewired to drive lineage-specific innovations across the bacterial domain.

cell differentiation↗
PubMed2024

Adaptation for Staphylococcus aureus to hosts via insertion mutation in the accessory gene regulator agrC gene: decreased virulence and enhanced persistence capacity.

UNLABELLED: Staphylococcus aureus is an important human pathogen due to its vast array of virulence factors regulated by multiple regulatory mechanisms, including the accessory gene regulator. In this study, two S. aureus strains were simultaneously isolated from the blood of a febrile patient, belonging to the same clone, designated as 23H with a complete hemolytic phenotype, and 23B, exhibiting an incomplete hemolytic phenotype. The genomic comparison between strains 23B and 23H revealed that 23B had a single adenine base insertion at position 923 in the agrC gene, leading to a functional loss of the encoded AgrC. Experimental findings showed that strain 23B had decreased hemolytic activity, lower cytotoxicity against human alveolar epithelial A549 cells and in the Galleria mellonella model, and a reduced ability to survive intracellularly after infecting macrophages, in comparison to 23H. Conversely, 23B exhibited enhanced biofilm formation, greater adherence to A549 cells, and increased persistence in the face of vancomycin and daptomycin treatment. Transcriptomic analysis revealed that 23B upregulated surface protein-encoding genes while simultaneously reducing the expression levels of virulence factors, highlighting the intricate regulatory adjustments facilitating its persistence and reducing pathogenic potential. ATP assay results indicated that 23B maintained elevated ATP levels during the exponential phase yet exhibited reduced levels in the stationary phase when compared with 23H. Our findings suggested that the mutation in the agrC gene of S. aureus results in diminished virulence but markedly enhances persistence. This mutated strain warrants clinical attention because it may lead to treatment failures and persist in patients. IMPORTANCE: In clinical antimicrobial therapy, bacterial strains often develop resistance to antimicrobial agents. Additionally, mutations in their gene regulatory networks can increase their persistence, especially in immunocompromised patients. This study identified an insertion mutation in the accessory gene regulator, agrC gene, carried by a Staphylococcus aureus strain isolated from the blood of a febrile patient, leading to the functional loss of AgrC. Further research revealed that despite the reduced virulence of the mutated strain, it significantly bolstered the capacity to adapt and endure within the host during prolonged infections. This was evidenced by increased adhesion and biofilm formation capabilities, development of antimicrobial tolerance, and decreased ATP levels linked to persistence. Therefore, monitoring these mutations in S. aureus is crucial clinically, as they can complicate treatment strategies.

Staphylococcus aureus↗
PubMed2026

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Humans↗
PubMed2026

Aldosterone suppresses Na+/H+ exchanger-3 expression through miR-204-5P-mediated posttranscriptional regulation in distal colon.

Na+/H+ exchanger-3 (NHE3) is a major mediator of electroneutral NaCl absorption in the intestine and colon. In the distal colon, chronic aldosterone exposure suppresses NHE3 expression, but the molecular mechanism responsible for this regulation remains unclear. Here, we tested whether aldosterone represses NHE3 through microRNA-dependent posttranscriptional regulation. Transcriptomic analysis of distal colon from dietary Na+-depleted rats identified miR-204-5P (miR-204-5P) as markedly upregulated. Aldosterone increased miR-204-5P abundance and concomitantly reduced NHE3 mRNA, protein expression, and transport activity in rat and human distal colonic epithelium and in SK-CO15 cells. Bioinformatic and reporter analyses identified a conserved miR-204-5P binding site within the NHE3 3'-untranslated region, and miR-204-5P mimic transfection markedly suppressed NHE3 expression and transport activity without affecting other Na+/H+ exchanger isoforms. These findings identify a previously unrecognized aldosterone-microRNA signaling pathway that mediates chronic repression of NHE3 and provide new insight into hormonal regulation of colonic Na+ absorption.NEW & NOTEWORTHY This study identifies a previously unrecognized aldosterone-microRNA signaling mechanism regulating colonic Na+ absorption. We demonstrate that aldosterone induces miR-204-5P, which directly targets the NHE3 3'-untranslated region and suppresses NHE3 expression and transport activity in distal colonic epithelium. These findings reveal a microRNA-mediated pathway linking mineralocorticoid signaling to long-term inhibition of electroneutral NaCl absorption, providing new insight into hormonal regulation of intestinal electrolyte transport.

Animals↗
PubMed2026

Ribonucleotide Reductase Inhibition Triggers Ferroptosis in Genetically Defined Subsets of Non-Small Cell Lung Cancer.

UNLABELLED: Non-small cell lung cancer (NSCLC) is responsible for the majority of cancer-related mortality worldwide. Lung adenocarcinoma is the most common NSCLC subtype. Despite advances in targeted therapies, treatment resistance remains a critical challenge. Ribonucleotide reductase (RNR), a crucial enzyme in deoxyribonucleotide triphosphate biosynthesis, is frequently upregulated in cancer, contributing to genomic instability and poor prognosis in multiple malignancies. However, the role of the RNR complex in driving tumorigenesis is not fully understood in oncogene-driven lung adenocarcinoma. Transcriptomic analysis of more than 27,000 real-world samples of patients with NSCLC revealed that RNR subunits (RRM1 and RRM2) are significantly upregulated in TP53-mutated NSCLC and are correlated with significantly poor prognosis in multiple oncogene-driven lung adenocarcinoma. Using pharmacologic and genetic approaches to inhibit RNR in lung adenocarcinoma models, we assessed functional consequences through molecular, biochemical, and imaging techniques. RNR inhibition induced appreciable replication stress and triggered DNA damage, leading to cell death in lung adenocarcinoma cells. Notably, we uncovered that RNR suppression preferentially induced ferroptosis, an iron-dependent cell death driven by lipid peroxidation. This represents a previously unrecognized mechanism of RNR-mediated cell death by which mutant lung adenocarcinoma cells can be selectively targeted. Our study establishes RNR inhibition as a potent strategy to selectively induce ferroptosis in oncogene-addicted lung adenocarcinoma, offering a new therapeutic avenue for genetically defined patient subgroups. Targeting nucleotide metabolism could serve as an effective approach to overcome treatment resistance and improve clinical outcomes for patients with high-risk lung adenocarcinoma. SIGNIFICANCE: Our findings highlight RNR as a promising therapeutic target in oncogene-driven lung adenocarcinoma. By demonstrating that RNR inhibition induces ferroptosis, our study opens up new possibilities for developing targeted therapies that selectively eliminate cancer cells in lung adenocarcinoma, paving the way for personalized treatment strategies and potentially overcoming resistance to current therapies.

Humans↗
PubMed2026

Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome.

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

Animals↗
PubMed2026

Systems genetics approaches model the heritable architecture of polyendocrine metabolic ovarian syndrome.

Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovered conserved genetic and environmental factors underlying PMOS, identified susceptible cell types and organs, and elucidated mechanisms linking PMOS to subsequent pathologies. For instance, we showed that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary-heart signaling circuits modulate cardiac function with aging. We further identified ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin, and glucose levels as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.

Female↗
PubMed2026

Downregulation of Trpv4 and Klf2 in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction.

Vascular cognitive impairment (VCI) shares major risk factors with heart failure with preserved ejection fraction (HFpEF), including obesity, diabetes and hypertension. Yet VCI research often relies on single-stimulus models, whereas patients experience combined risk factors. We therefore assessed cerebrovascular and cognitive phenotypes in an HFpEF model and investigated underlying mechanisms. Male Lean and Obese ZSF1 rats underwent longitudinal assessments of blood pressure, glucose, cardiac function and behavioural performance. Cerebral blood flow and neurovascular coupling were assessed by laser speckle contrast imaging. White matter integrity, blood-brain barrier (BBB) permeability and vascular density were analyzed by (immuno)histochemistry. Cortical microvessels were isolated for transcriptomic profiling, and selected targets were validated using multiplex in-situ hybridization. Obese rats exhibited neurovascular uncoupling and impaired short- and long-term memory and spatial learning, accompanied by brain atrophy and reduced myelin. BBB permeability increased at 22-23 weeks and vascular density at 34-35 weeks in Obese versus Lean rats. Transcriptomic analysis of brain microvessels revealed altered processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling, with consistent downregulation of Trpv4 and Klf2. Obese ZSF1 rats develop progressive neurovascular dysfunction associated with HFpEF onset and reduced Trpv4 and Klf2 expression in cerebral microvessels, two key vasoprotective genes.

Diastolic dysfunction↗
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↗
PubMed2025

ALDOC and PGK1 coordinately induce glucose metabolism reprogramming and promote development of colorectal cancer.

Colorectal cancer (CRC) remains a significant health challenge globally, demanding a comprehensive understanding of its molecular underpinnings for effective management. In this study, we investigated the role of Aldolase C (ALDOC), a glycolytic enzyme, in CRC pathogenesis. Transcriptomic analysis of CRC tissues from The Cancer Genome Atlas (TCGA) revealed a substantial upregulation of ALDOC, correlating with adverse clinical outcomes. Immunohistochemical (IHC) staining of locally collected patient-derived tissues corroborated these findings, demonstrating elevated ALDOC expression in tumor tissues, particularly in advanced stages. Functional studies elucidated the regulatory role of ALDOC in CRC cell phenotypes. ALDOC knockdown significantly inhibited cell proliferation, induced apoptosis, arrested cell cycle progression, and suppressed cell migration in vitro. Moreover, in vivo studies using xenograft models confirmed that ALDOC knockdown attenuated tumor growth. Mechanistically, ALDOC was found to interact with hypoxia-inducible factor 1 alpha (HIF1A) and enhance its transcriptional activity on phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme. Dual-luciferase reporter assays and chromatin immunoprecipitation experiments validated the ALDOC-mediated transcriptional activation of PGK1. Further functional rescue experiments revealed a synergistic interplay between ALDOC and PGK1 in regulating CRC cell phenotypes. Additionally, ALDOC was implicated in promoting aerobic glycolysis in CRC cells, potentially through PGK1 regulation. Collectively, our findings unveil ALDOC as a critical regulator of CRC pathogenesis, offering insights into its potential as a therapeutic target and highlighting the ALDOC/PGK1 axis as a promising avenue for further investigation in CRC.

Humans↗