Molecular Genetics and Genomics最新文献

The pig serves as both an important agricultural species and a valuable biomedical model due to its physiological and immunological similarities to humans. RNA editing, especially adenosine-to-inosine (A-to-I) conversions, is a key post-transcriptional mechanism that regulates gene expression and immune responses. However, the dynamics of RNA editing during porcine spleen development are still underexplored. To address this, we systematically profiled the RNA editing landscape of Ningxiang pig spleens at three developmental stages (30, 90, and 210 days) to investigate the dynamic regulation of RNA editing during immune system maturation. A total of 72,182 high-confidence RNA editing sites were identified, of which 92.9% corresponded to A-to-I conversions. These sites were predominantly located within swine-specific SINE retrotransposons (PRE-1/Pre0_SS). Across developmental stages, 2,649 sites exhibited significant differential editing, indicating that RNA editing activity is dynami-cally regulated during spleen development. Functional enrichment analysis of the differentially edited genes revealed enrichment in immune-related pathways, particularly those involved in T cell activation, cytokine signaling, and antiviral defense. Protein-protein interaction analysis further revealed two key RNA-editing-associated modules centered on PTPN11 and EP300, underscoring regulatory of immune signaling and disease response. Collectively, these results demonstrate that RNA editing constitutes a dynamic and developmentally regulated post-transcriptional layer during spleen development. Our findings highlight RNA editing as an important regulatory mechanism contributing to immune maturation and provide a valuable resource for future studies on immune regulation and disease resistance in pigs.

Microbial degradation of cellulose is a fundamental process driving the global carbon cycle and holds immense potential for sustainable biotechnology; however, the genomic mechanisms and transcriptional regulation underlying this capability in marine environments remain largely underexplored. To decipher these complex biological strategies, we isolated the novel strain JC1303 from marine sediments and integrated whole-genome sequencing with transcriptomic analysis to systematically characterize its enzymatic arsenal and metabolic adaptations. Whole-genome sequencing revealed that strain JC1303 possesses a circular chromosome of 4.37 Mb in length, with a GC content of 67.41%. Phylogenetic analyses based on the 16 S rRNA gene and whole-genome data suggest that strain JC1303 likely represents a new species within the genus Pseudoxanthomonas. Pan-genome analysis of the genus demonstrates a typical "open" genome architecture with only 3% conserved core genes, highlighting high evolutionary plasticity. In contrast, strain JC1303 has 936 unique genes significantly enriched in metabolism (163 genes) and signal transduction (138 genes), providing a molecular basis for its adaptation to the cellulose degradation niche. Genome mining identified a complete cellulolytic system comprising three endo-β-1,4-glucanases, two cellulase, and four β-1,4-glucosidase, supported by glycolysis/gluconeogenesis, TCA cycle, pentose phosphate pathway, amino acid synthesis pathways, ABC transport systems, and the respiratory chain. Crucially, comparative transcriptomic profiling under cellulose induction validated the functional execution of this genetic potential. Among 1465 differentially expressed genes, the strain exhibited a coordinated strategy: while distinct isozymes were downregulated, a key endoglucanase gene (JC1303_01352) and multiple membrane transporter genes were significantly upregulated. This suggests a specific mechanism coupling extracellular hydrolysis with efficient substrate uptake. In conclusion, this study not only elucidates the genetic blueprint and transcriptional regulation of a new marine cellulolytic species Pseudoxanthomonas JC1303 but also offers theoretical support for engineering robust biocatalysts.

Aflatoxin B1 (AFB1) is a potent mycotoxin that threatens food safety and human health. This study investigated the capacity of yeast isolates to tolerate and detoxify AFB1 and performed genomic characterization of the most active strain. Among several Pichia and Wickerhamomyces isolates, Pichia kudriavzevii RWT exhibited the strongest tolerance, maintaining growth at AFB1 concentrations up to 200 ppb and decontaminating 26.5% of AFB1 within six hours, more than twice the reduction achieved by the next best isolate. In contrast, heat-killed yeast cells showed no significant reduction activity. This suggests that cell wall adsorption alone is insufficient for meaningful AFB1 reduction in this strain and highlights the importance of enzymatic or transporter-mediated mechanisms that require live, metabolically active cells. Whole-genome sequencing of RWT yielded a 10.86 Mb assembly with 5,445 predicted proteins grouped into 4,274 orthologous clusters, sharing 2,448 core clusters with related yeasts but retaining 953 clusters unique to Pichia species. Functional annotation highlighted genes potentially involved in AFB1 detoxification, including predicted cytochrome P450, epoxide hydrolase (LAP2), glutathione-S-transferase (URE2), and the ABC transporter (YCF1), suggesting pathways for AFB1 activation, glutathione conjugation, and vacuolar sequestration. AFB1 treatments were found to increase the gene expression of those key genes involved in AFB1 detoxification. Comparative genomics confirmed that RWT's genome size and core gene content are typical of P. kudriavzevii, while its unique clusters are enriched in membrane transport, stress response, and metal-ion binding functions. These findings position P. kudriavzevii RWT as a promising candidate for biological AFB1 mitigation, providing a genetic basis for its robust detoxification capacity.

Dysregulated epigenetic control and DNA-repair defects are hallmarks of many cancers and neurodevelopmental disorders. ZMYM3, a chromatin-associated zinc-finger protein, orchestrates histone deacetylation, BRCA1-dependent homologous recombination (HR), and cytoskeletal organisation, yet the post-translational mechanisms that govern its activity remain largely unknown. Here we integrate global phosphoproteomics data to define the regulatory landscape of ZMYM3, with a focus on the highly recurrent phosphosite S464 located in its zinc-finger domain. S464 is detected in > 50% of curated human-cell-line datasets and is co-regulated with four upstream kinases (CDK13, HIPK1, CDK9, CLK3) and 15 binary interactors including BRCA1, HDAC6, and SWI/SNF components. Positively co-phosphorylated networks are enriched for chromatin remodelling, mitotic segregation, DNA-damage response, and cytoskeletal dynamics. cProSite analysis of patient tumours reveals striking S464 hyper-phosphorylation in breast and ovarian cancers, correlating with HR-deficiency signatures. ZMYM3 S464 emerges as a phospho-regulatory hub that coordinates epigenetic silencing, HR repair, and mitotic fidelity. Its cancer-type-specific upregulation offers a novel biomarker for HR-deficiency stratification and a therapeutic entry point for modulating BRCA1 function or epigenetic drug sensitivity; functional validation in HR-deficient models is now warranted.

Sleep is a ubiquitous phenomenon throughout the animal kingdom; nonetheless, its evolutionary origins remain mostly enigmatic. Comprehending the origins of the biological systems governing sleep necessitates methodologies that extend beyond comparisons of current animals and instead investigate the profound history of their molecular underpinnings. This study used a molecular paleobiology framework toexamine the evolutionary origins of sleep-related genes by mapping their homologs onto the reconstructed genome of the Last Universal Common Ancestor (LUCA). Utilizing phylogenomic reconstruction and functional enrichment studies, we ascertain that multiple gene families crucial for human sleep, especially those governing circadian timing, fundamental metabolism, and cellular signaling, were extant in this ancient progenitor. The results substantiate the perspective that the chemical elements facilitating sleep did not arise as new innovations but rather evolved from ancient cellular systems that initially served fundamental physiological roles. Our research demonstrates a profound evolutionary pathway in which the intricacy of sleep developed through the incremental co-option and amalgamation of conserved genomic modules. This study presents a novel viewpoint on the emergence of essential physiological activities from primordial and universal biological mechanisms.

Preterm birth (PTB) is a leading cause of prenatal and infant mortality and morbidity, yet its molecular mechanisms remain poorly understood. This systematic review aims to enhance understanding of PTB's molecular genetics and to identify potential biomarkers and therapeutic targets by comprehensively analyzing genetic association studies conducted among Asian populations. A systematic search was performed across six online databases, including Google Scholar, Science Direct, Clinical Trials, PubMed, Cochrane, and MyCite, using a combined search strategy of PTB, gene polymorphisms, and Asia (PROSPERO protocol: CRD42023458957). Peer-reviewed articles focusing on the effects of genetic association on labor progression in the Asian population were included. Subsequently, data extraction encompassing study design, demographics, genetic determinants, and effect estimates were collected. Quality assessment was conducted for each study using the Quality of Genetic Association Studies (Q-Genie) tool. Due to heterogeneity among study designs, genetic variants, and reported outcomes, a meta-analysis was not performed; instead, a systematic narrative synthesis was conducted. Out of 2,412 screened articles, 16 met the inclusion criteria and passed the Q-Genie quality assessment. These studies collectively investigated 37 polymorphisms within 25 genes across various Asian ethnic groups. These genes exhibited associations with various aspects of PTB, shedding light on the roles of innate immune responses, inflammation, myometrial quiescence, oxidative stress, and uteroplacental blood flow in PTB pathogenesis. This review highlights the role of genetics role in PTB susceptibility across Asian populations and the need to explore candidate genes and their interactions to uncover the underlying molecular mechanisms.

Lipid-associated disorders such as obesity are major global health challenges, primarily driven by dysregulated lipid metabolism and associated alterations in gene expression and protein interactions. Understanding these molecular mechanisms is essential for identifying new therapeutic targets. This study investigates the molecular landscape of lipid dysregulation through differential gene expression analysis in hyperlipidemic rat models. By integrating multiple datasets and computational tools, we aimed to identify key proteins involved in obesity pathogenesis, thereby contributing to the development of targeted therapeutic strategies for lipid-associated disorders. A comprehensive search was conducted to identify differentially expressed genes associated with lipid disorders by analyzing metadata from various public databases, leading to the curation of four distinct datasets. Gene Ontology (GO) analysis was performed using the G: Profiler server, and protein-protein interaction (PPI) networks were constructed using Cytoscape. Cluster analysis with MCODE identified densely connected subnetworks, while pathway enrichment analysis using KEGG-KASS explored gene involvement in biological pathways. GO analysis revealed critical pathways involved in lipid metabolism, particularly those related to lipid oxidation and homeostasis. Pathway enrichment analysis identified three pivotal genes-Akt1, Nr1h3, and Il6-with Nr1h3 emerging as a prominent target under treatment conditions. Il6 showed significance in both disease and treatment contexts, suggesting its potential as a therapeutic target. These genes were also linked to obesity, fatty liver disease, and atherosclerosis in rat datasets, with supporting evidence from previously published rodent and human studies.

Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%). Koolen-de Vries syndrome (KdVS), an autosomal dominant NDD caused by KANSL1 haploinsufficiency, exemplifies this diagnostic challenge with its multisystem manifestations and lack of systematic genotype-phenotype associations. To address this gap, we constructed a comprehensive KdVS genotype-phenotype repository by systematically integrating all molecularly confirmed cases from global literature. Comprehensive phenotypic analysis revealed that core KdVS features include developmental delay/intellectual disability, characteristic craniofacial dysmorphism, hypotonia, and multisystem abnormalities. Phenotypic association analysis identified 249 significant correlations, demonstrating that KdVS clinical manifestations are highly interconnected rather than representing isolated features, such as the association between strabismus and hydrocephalus (OR = 14.26). Application of this repository to screen a Chinese rare disease cohort identified 53 KANSL1 variants. Among these, one de novo nonsense variant (NM_001193466.2: c.902T > G, p.Leu301Ter) was classified as pathogenic in a Chinese boy with classic KdVS features. The remaining 52 variants were categorized as variants of uncertain significance (VUS), approximately half of which were absent from gnomAD databases. Each VUS was comprehensively annotated with detailed clinical profiles to facilitate phenotype-driven reinterpretation. In conclusion, this study establishes KdVS as a highly interconnected multisystem disorder and demonstrates that deep phenotypic association analysis enhanced genetic diagnosis. This disease-specific repository approach provides a scalable framework for improving molecular diagnostics across rare NDDs.

Citrobacter koseri is a Gram-negative, multidrug-resistant bacterium linked to severe infections in immunocompromised individuals and neonates. It is especially linked to sepsis and meningitis, which often lead to CNS abscesses in newborns. Most infections happen randomly, but some are passed down from parent to child. There have also been reports of hospital-acquired outbreaks in neonatal care units. Even though diagnostic and treatment methods have improved, the death rate is still high. About one in three affected babies dies, and almost half of them suffer long-term neurological damage. As antibiotic resistance becomes more common, there is a growing need to look into new ways to treat diseases, such as vaccines and new drug targets. In order to address this issue, a thorough in-silico methodology integrating subtractive proteomics and reverse vaccinology was employed to pinpoint potential therapeutic targets from the core proteome. Five multi-epitope vaccine constructs were created using B- and T-cell epitopes from prioritized proteins, based on epitope prediction. Physicochemical and docking analysis identified constructs V1 and V5 as having strong binding affinities to Toll-like receptors TLR4 and TLR2, respectively. Furthermore, MD simulations validated the structural stability of docked complexes. In-silico immune simulations revealed that the constructs might induce robust immune responses. Additionally, potential drug target proteins were subjected to druggability analysis. This study presents a promising computational framework for combating C. koseri, though experimental and animal model validations are necessary to confirm the findings of this study.