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PubMed2025

The common murine retroviral integration site activating Hhex marks a distal regulatory enhancer co-opted in human early T-cell precursor leukemia.

The Hhex gene encodes a transcription factor that is important for both embryonic and post-natal development, especially of hematopoietic tissues. Hhex is one of the most common sites of retroviral integration in mouse models. We found the most common integrations in AKXD (recombinant inbred strains) T-ALLs occur 57-61kb 3' of Hhex and activate Hhex gene expression. The genomic region of murine leukemia virus (MLV) integrations has features of a developmental stage-specific cis regulatory element (CRE), as evidenced by ATAC-seq in murine progenitor cells and high H3K27 acetylation at the syntenic CRE in human hematopoietic cell lines. With ChIP-exonuclease, we describe occupancy of LIM domain binding protein 1 (LDB1), the constitutive partner of the LIM Only-2 (LMO2), GATA1, and TAL1 transcription factors at GATA sites and at a composite GATA-E box within the CRE. With virtual 4C analysis, we observed looping between this +65kb CRE and the proximal intron one enhancer of HHEX in primary human ETP-ALLs and in normal progenitor cells. Our results show that retroviral integrations at intergenic sites can mark and take advantage of CREs. Specifically, in the case of HHEX activation, this newly described +65kb CRE is co-opted in the pathogenesis of ETP-ALL by the LMO2/LDB1 complex.

Humans↗

PubMed2026

O'nyong-nyong virus adaptive mutations in non-structural protein 1 and 3 enhance RNA replication and overcome FHL1 requirement.

Arthritogenic alphaviruses, like o'nyong-nyong virus (ONNV), cause debilitating musculoskeletal diseases and are geographically expanding. To predict their emergence, we seek to better understand evolutionary mechanisms that enable changes in virus tropism. Here, we identify adaptive mutations in the ONNV non-structural proteins (nsPs) that arose during cellular serial passaging and enabled ONNV to infect non-permissive Lunet cells. Using shotgun proteomics, we show that this human hepatoma cell line lacks the four-and-a-half-LIM domain protein 1 (FHL1), an essential host factor in ONNV RNA replication. Individual single nucleotide mutations in the nsP1 ring-aperture membrane-binding and oligomerization domain, the nsP3 macrodomain, and the nsP3 opal stop codon overcome FHL1 deficiency in Lunet cells by enhanced RNA replication. These findings demonstrate how subtle genomic changes in nsPs can profoundly influence alphavirus replication and tropism.

LIM Domain Proteins↗

PubMed2024

Knockdown Proteomics Reveals USP7 as a Regulator of Cell-Cell Adhesion in Colorectal Cancer via AJUBA.

Ubiquitin-specific protease 7 (USP7) is implicated in many cancers including colorectal cancer in which it regulates cellular pathways such as Wnt signaling and the P53-MDM2 pathway. With the discovery of small-molecule inhibitors, USP7 has also become a promising target for cancer therapy and therefore systematically identifying USP7 deubiquitinase interaction partners and substrates has become an important goal. In this study, we selected a colorectal cancer cell model that is highly dependent on USP7 and in which USP7 knockdown significantly inhibited colorectal cancer cell viability, colony formation, and cell-cell adhesion. We then used inducible knockdown of USP7 followed by LC-MS/MS to quantify USP7-dependent proteins. We identified the Ajuba LIM domain protein as an interacting partner of USP7 through co-IP, its substantially reduced protein levels in response to USP7 knockdown, and its sensitivity to the specific USP7 inhibitor FT671. The Ajuba protein has been shown to have oncogenic functions in colorectal and other tumors, including regulation of cell-cell adhesion. We show that both knockdown of USP7 or Ajuba results in a substantial reduction of cell-cell adhesion, with concomitant effects on other proteins associated with adherens junctions. Our findings underlie the role of USP7 in colorectal cancer through its protein interaction networks and show that the Ajuba protein is a component of USP7 protein networks present in colorectal cancer.

Ubiquitin-Specific Peptidase 7↗

PubMed2025

LIMA1 inhibits cisplatin resistance and malignant biological behavior of bladder cancer cells by suppressing the Wnt/β-catenin pathway.

OBJECTIVE: This study aimed to explore the effect of LIM domain and actin binding 1 (LIMA1) on bladder cancer (BCa) cells and to investigate its underlying molecular mechanisms. METHODS: The expression of LIMA1 gene in clinical BCa tissue samples and BCa cell models was detected using real-time quantitative PCR and western blot. Subsequently, LIMA1 knockdown experiments were performed exclusively in the BCa J82 cell line, while LIMA1 overexpression was conducted only in the cisplatin-resistant J82/CR cell line. The proliferation of the cells was assessed by colony formation assay. Cisplatin resistance was evaluated by MTT assay. Migration and invasion of the cells were tested by Transwell assay. Additionally, the levels of key proteins in the Wnt/β-catenin signaling pathway were examined by western blotting. RESULTS: We found that LIMA1 was underexpressed in BCa tissues and cells (P < 0.01). Overexpression of LIMA1 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of BCa cells (P < 0.01) and improved their cisplatin resistance (P < 0.01), whereas knocking down LIMA1 produced opposite results (P < 0.01). Furthermore, overexpression of LIMA1 could suppress the Wnt/β-catenin signaling pathway in BCa cells (P < 0.01), and activation of this pathway partially reversed the anti-tumor effects produced by overexpression of LIMA1 (P < 0.01). CONCLUSION: LIMA1 could inhibit the malignant biological behavior of BCa cells and weaken their cisplatin resistance by negatively regulating the Wnt/β-catenin signaling pathway. Our findings provide new insights for the clinical treatment of BCa.

Humans↗

PubMed2026

PDLIM4 promotes dephosphorylation of STAT transcription factors by recruiting PTP-BL and inhibits Th1, Th2, and Th17 cell differentiation.

STAT (signal transducers and activators of transcription) transcription factors are activated by tyrosine phosphorylation after cytokine stimulation and are critical for the differentiation of T-helper (Th) cells into particular Th lineage subsets. How STAT-mediated Th cell differentiation is negatively regulated, however, is not fully understood. Here, we report that PDLIM4 binds to STAT3, 4, and 6 and suppresses gene activation mediated by these STATs. PDLIM4 acts as an adaptor that recruits PTP-BL, a protein tyrosine phosphatase, through its LIM (abnormal cell lineage 11-islet 1-mechanosensory abnormal 3) domain, facilitating dephosphorylation of STAT proteins. PDLIM4-deficiency in CD4+ T cells resulted in augmented tyrosine phosphorylation of these STAT proteins and consequently enhanced Th1, Th2, and Th17 cell differentiation, suggesting that PDLIM4 regulates the differentiation of multiple lineages of Th cells by suppressing STAT signaling. We further found that a non-synonymous single-nucleotide polymorphism in PDLIM4, which causes the substitution of a glycine residue with a cysteine in the LIM domain, is associated with susceptibility to rheumatoid arthritis and Graves' disease, both of which are known to be Th17 cell-driven autoimmune diseases. Notably, PDLIM4 containing this amino acid substitution in the LIM domain showed reduced binding to PTP-BL and was therefore partially impaired in its ability to dephosphorylate STAT3 and suppress STAT3 signaling. Our findings define an essential role of PDLIM4 in negatively regulating STAT-mediated Th-cell differentiation and preventing the onset of human autoimmune diseases.

Animals↗

PubMed2025

GATA2 promotes cervical cancer progression under the transcriptional activation of TRIP4.

The continued rise in recurrence and mortality rates of cervical cancer suggests the need to find novel therapeutic targets. Previous studies suggest that TRIP4 acts as a transcription factor to regulate cervical carcinogenesis and progression. Our aim was to explore whether the key downstream genes of TRIP4 functions same as TRIP4 in promoting cervical cancer development. We analyzed and confirmed the downstream targets of TRIP4 by RNA sequencing in cervical cancer cells with TRIP4 knockdown. The expression correlation between TRIP4 and GATA2 and the effect of GATA2 on cervical cancer cell growth were determined respectively by Western Blot, Scratch, Spheroid, and MTT analyses. Pulldown and ChIP experiments were performed to analyze the binding of TRIP4 to the promoter of GATA2. The clinical significance of GATA2 and TRIP4 expression in cervical cancer patients was analyzed by tissue microarray staining. GATA2 was highly expressed in cervical cancer tissues. Knockdown of GATA2 inhibited the growth, metastasis and stemness of cervical cancer cells and sensitized cervical cancer cells to radiation therapy. The inhibitory effect of TRIP4 knockdown on cervical cancer cells was rescued by GATA2 overexpression. Furthermore, TRIP4 could bind to the specific GATA2 promoter region, thereby activating its transcription. Clinical tissue microarray analysis indicated that the expression of TRIP4 and GATA2 was positively correlated, and high expression of both predicted a poor prognosis in cervical cancer patients. Our study demonstrated that GATA2 functions as the key downstream target of TRIP4 to promote cervical cancer progression and effective intervention of TRIP4/GATA2 signaling is expected to be developed as potential cervical cancer therapeutic strategy.

Humans↗

PubMed2026

Gut microbial diversity at baseline conditions the clinical, microbiome, and metabolic response to paraprobiotic Lactiplantibacillus plantarum LRCC5282 in overweight adults.

The gut microbiota is increasingly recognized as a target for obesity management; however, whether baseline gut microbial diversity conditions responsiveness to microbiota-targeted interventions remains unclear. We aimed to investigate whether baseline gut microbial diversity is associated with responsiveness to a paraprobiotic derived from Lactiplantibacillus plantarum LRCC5282 (LP5282-P) in overweight adults. In a 12-week, randomized, double-blind, placebo-controlled, multicenter trial of 120 overweight adults, LP5282-P produced no significant between-group differences in any clinical outcome across the overall per-protocol population. However, in the low-diversity subgroup, LP5282-P was associated with significant reductions in body weight, body mass index, and circulating leptin levels. These clinical changes were accompanied by compositional shifts in the gut microbiota, including higher relative abundances of Christensenellaceae, Faecalibacterium, and Alistipes. Fecal metabolite profiles showed elevated acetate and butyrate concentrations and altered bile acid composition. Within the low-diversity subgroup, changes in the relative abundances of Akkermansia and Eubacterium were inversely correlated with changes in body weight, body fat mass, and leptin levels. In contrast, the high-diversity subgroup exhibited no consistent response across the outcome domains examined. Overall, baseline gut microbial diversity was associated with differential responsiveness to LP5282-P, supporting its potential use as a stratification variable in future microbiota-targeted intervention trials. Further studies integrating direct measures of microbial activity and host response are warranted to elucidate the biological pathways underlying this diversity-dependent responsiveness. Trial registration: Clinical Research Information Service (CRIS), KCT0008119.

Humans↗

PubMed2025

Characterization of group I introns in generating circular RNAs as vaccines.

Circular RNAs are an increasingly important class of RNA molecules that can be engineered as RNA vaccines and therapeutics. Here, we screened eight different group I introns for their ability to circularize and delineated different features that are important for their function. First, we identified the Scytalidium dimidiatum group I intron as causing minimal innate immune activation inside cells, underscoring its potential to serve as an effective RNA vaccine without triggering unwanted reactogenicity. Additionally, mechanistic RNA structure analysis was used to identify the P9 domain as important for circularization, showing that swapping sequences can restore pairing to improve the circularization of poor circularizers. We also determined the diversity of sequence requirements for the exon 1 and exon 2 (E1 and E2) domains of different group I introns and engineered a S1 tag within the domains for positive purification of circular RNAs. In addition, this flexibility in E1 and E2 enables substitution with less immunostimulatory sequences to enhance protein production. Our work deepens the understanding of the properties of group I introns, expands the panel of introns that can be used, and improves the manufacturing process to generate circular RNAs for vaccines and therapeutics.

RNA, Circular↗

PubMed2026

Induced Pluripotent Stem Cells in Non-Model Species: Applications and Challenges.

Induced pluripotent stem cells have revolutionized biomedical research-yet the vast majority of life on Earth remains beyond their reach. Non-model species lack the annotated genomes, validated reagents, and species-specific culture infrastructure that make iPSC technology routine in humans and mice, and this infrastructure deficit, compounded by genuine biological differences in pluripotency network architecture across taxa, is what has kept the field narrow. The deep conservation of the core pluripotency network across vertebrates suggests that reprogramming may, in principle, be achievable across a far broader range of species than currently demonstrated-though the extent to which this holds across more divergent taxa remains to be established. This review consolidates current progress and future potential of iPSC technology across five domains: technical reprogramming challenges and advances; conservation applications including genetic rescue, in vitro gametogenesis, and de-extinction; medical applications within a one medicine framework; agricultural applications spanning disease resistance, climate resilience, and cultured meat; and species-specific iPSC-derived systems in ecotoxicology. Throughout, we distinguish what has been demonstrated from what remains aspirational and identify the priorities that will determine whether the iPSC revolution can be extended-rigorously and at scale-beyond model organism research.

Induced Pluripotent Stem Cells↗

PubMed2026

Beyond multidimensionality: a systematic review of recurrent frailty archetypes in community-dwelling older adults.

BACKGROUND: Frailty is a clinically heterogeneous geriatric syndrome commonly summarised using physical or multidomain severity scores. Whether person-centred analyses identify recurring within-frailty configurations has not been systematically examined in community-dwelling older adults. METHODS: We searched PubMed, Embase, MEDLINE, and CINAHL (January 2000-November 2025) for cross-sectional studies using latent class, latent profile, or analogous clustering methods to derive frailty subgroups. Quality was assessed using the AHRQ checklist and a purpose-built appraisal of person-centred model reporting. Study-derived classes were mapped in duplicate to a structured archetype framework developed through comparison of class-defining features across studies. RESULTS: Fourteen reports representing 12 independent datasets from eight countries were included. Six configurations were identified: minimally impaired reference, mobility-physical, nutritional-metabolic, cognitive-predominant, combined cognitive-physical, and psychosocial/mood-predominant. Convergence was measurement-dependent. The reference and mobility-physical configurations recurred across physical-only and multidomain indicator sets, while the combined cognitive-physical configuration appeared across several multidomain frameworks but required cognition to be measured. The remaining configurations emerged only when their defining domains were included. Evidence of prognostic value beyond aggregate frailty severity came from one deficit-index study. Collapsing shared-provenance reports and excluding the boundary-eligible study did not alter recurrence; excluding the Croatian dataset left five configurations recurrent, with the cognitive-predominant configuration supported by one independent dataset. CONCLUSIONS: Person-centred analyses identify recurring within-frailty configurations, but their apparent stability is partly measurement-dependent. A five-configuration core persisted after exclusion of the Croatian dataset, whereas the cognitive-predominant configuration remained weakly replicated. Harmonised indicators and rigorous external validation are needed before clinical application.

Humans↗

PubMed2026

Oxygen-dependent subcellular redistribution of PHD3 links the hypoxic microenvironment to mitochondrial metabolic reprogramming in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic dysregulation, with both prolyl hydroxylase domain protein 3 (PHD3) and pyruvate carboxylase (PC) independently implicated in disease progression. Although each influences patient outcomes, a direct mechanistic interplay between these two regulators has remained elusive. Here, we uncover a novel regulatory axis involving PHD3 and PC by identifying an unexpected subcellular behavior of PHD3, namely, its dual localization to the cytosol and the mitochondrial matrix. We show that mitochondrial import of PHD3 is associated with its intracellular clustering, a process modulated by PHD3 hydroxylase activity and oxygen levels. Once in the matrix, PHD3 directly hydroxylates PC, suppressing its enzymatic activity. In ccRCC with elevated PHD3 expression, this modification restricts anaplerotic flux into the tricarboxylic acid cycle, leading to impaired proliferation, reduced metastasis, and enhanced apoptosis. Together, our findings provide a new framework for targeting cancer metabolism by establishing a previously unrecognized mechanistic link between PHD3-mediated oxygen sensing within the tumor microenvironment and the regulation of ccRCC mitochondrial metabolism through the subcellular re-localization of PHD3.

Journal Article↗

PubMed2026

Programmable antibody-based chimeric entry receptors for sarbecoviruses.

Despite frequent spillover of sarbecoviruses, most SARS-related viruses discovered in animals fail to engage human ACE2 (hACE2), limiting mechanistic insight and risk assessment. Here we developed antibody-based chimeric entry receptors (ABCERs) that reprogram antibody-antigen recognition into a synthetic, cell-anchored receptor interface. By replacing the extracellular protease domain of hACE2 with single-chain variable fragments (scFvs) from broadly neutralizing antibodies, ABCERs mimic viral receptor engagement while preserving the intracellular architecture required for cathepsin L-dependent endocytic fusion. This modular design converts antibody specificity into a programmable entry module, supporting efficient infection and replication of diverse sarbecoviruses from both clinical and animal sources. Among the tested scFvs, E7 exhibited exceptional breadth, recognizing conserved epitopes shared across representative sarbecoviruses from all clades. Sera from Pfizer-BioNTech mRNA-vaccinated individuals potently blocked E7 binding to SARS-CoV-2 but showed limited cross-inhibition of E7 interactions with RBDs from hACE2-independent sarbecoviruses, revealing a substantial gap in current vaccine-induced humoral immunity. Together, our findings establish E7-based ABCERs as a programmable synthetic receptor platform that bridges antibody recognition and viral propagation, offering a universal tool for isolating, studying, and surveying sarbecoviruses beyond the hACE2-dependent paradigm.

Humans↗

PubMed2025

Identification of novel PfEMP1 variants containing domain cassettes 11, 15 and 8 that mediate the Plasmodium falciparum virulence-associated rosetting phenotype.

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a diverse family of variant surface antigens, encoded by var genes, that mediates binding of infected erythrocytes to human cells and plays a key role in parasite immune evasion and malaria pathology. The increased availability of parasite genome sequence data has revolutionised the study of PfEMP1 diversity across multiple P. falciparum isolates. However, making functional sense of genomic data relies on the ability to infer binding phenotype from var gene sequence. For P. falciparum rosetting, the binding of infected erythrocytes to uninfected erythrocytes, the analysis of var gene/PfEMP1 sequences encoding the phenotype is limited, with only eight rosette-mediating PfEMP1 variants described to date. These known rosetting PfEMP1 variants fall into two types, characterised by N-terminal domains known as "domain cassette" 11 (DC11) and DC16. Here we test the hypothesis that DC11 and DC16 are the only PfEMP1 types in the P. falciparum genome that mediate rosetting, by examining a set of thirteen recent culture-adapted Kenyan parasite lines. We first analysed the var gene/PfEMP1 repertoires of the Kenyan lines and identified an average of three DC11 or DC16 PfEMP1 variants per genotype. In vitro rosette selection of the parasite lines yielded four with a high rosette frequency, and analysis of their var gene transcription, infected erythrocyte PfEMP1 surface expression, rosette disruption and erythrocyte binding function identified four novel rosette-mediating PfEMP1 variants. Two of these were of the predicted DC11 type (one showing the dual rosetting/IgM-Fc-binding phenotype), whereas two contained DC15 (DBLα1.2-CIDRα1.5b) a PfEMP1 type not previously associated with rosetting. We also showed that a Thai parasite line expressing a DC8-like PfEMP1 binds to erythrocytes to form rosettes. Hence, these data expand current knowledge of rosetting mechanisms and emphasize that the PfEMP1 types mediating rosetting are more diverse than previously recognised.

Plasmodium falciparum↗

PubMed2026

Spacer-engineered donor DNA enhances CRISPR-Cas9-mediated knockin to establish a chemical knockdown platform for endogenous proteins.

Precise installation of functional protein domains at endogenous loci is a powerful approach for interrogating protein functions, but its broad application is limited by the low efficiency of homology-directed repair (HDR)-mediated knockin during Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 gene editing. Here, we investigated a simple donor DNA engineering strategy that enhances HDR-mediated gene knockin by appending additional gRNA-recognizable spacer sequences to donor templates. Systematic analysis of linear dsDNA and plasmid donors showed that spacer position, length, and orientation influenced HDR efficiency, and that spacer-containing donors improved knockin across multiple genomic loci, insertion sizes, cell types and delivery modalities. Mechanistic analyses revealed that spacer-containing donors formed stable complexes with Cas9/gRNA and showed increased nuclear localization, supporting nuclear delivery as a key contributor to improved editing outcomes. We then applied this gene-editing strategy to establish a chemical knockdown platform by installing drug-responsive degrons at endogenous loci, generating cell lines in which GSK3β or Lin28A protein could be rapidly, potently and reversibly depleted by drug treatment. These platforms enable selective modulation of endogenous proteins and reveal cellular responses that may differ from those obtained using conventional genetic perturbation. Together, this work establishes a readily implementable framework that integrates improved gene editing with on-demand chemical knockdown of endogenous proteins.

CRISPR-Cas9↗

PubMed2026

Subnuclear genome compartmentalization controls bivalent chromatin activity.

The nuclear genome is spatially organized into a three-dimensional architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how higher-order spatial genome architecture regulates human development has been overlooked, and the interplay between chromatin state and subnuclear genome compartmentalization is poorly understood. Here we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from mid-gestational human cortex, identifying an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, subnuclear genome compartmentalization is extensively remodelled, relocating hundreds of neuronal genes from the lamina to speckles, including key neurodevelopmental genes bivalent for trimethylation of histone H3 at Lys27 (H3K27me3) and Lys4 (H3K4me3). At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 monovalency and increases transcription more than eightfold. We further demonstrate that proximity to the nuclear periphery-not the presence of H3K27me3-maintains the lowly expressed, poised state of bivalent genes embedded in the lamina. We find that the repressive environment of the lamina is associated with spatial segregation of the transcriptional elongation machinery from the nuclear periphery. Our results establish a paradigm in which knowing the spatial location of a gene is necessary for understanding its epigenomic regulation.

Humans↗