Frontiers in Genetics最新文献

Introduction: Cardiovascular disease (CVD) is a major threat to health, with high incidence rates and a trend toward younger age groups. RNA modifications are an important component of epigenetics, widely present and indispensable in cells. Increasing evidence suggests that RNA modifications are key regulatory factors involved in cardiac physiological and pathological changes. Understanding the role of RNA modifications in heart-related diseases can help us to identify new drug targets.

Methods: To systematically investigate the role of m6A modification in different cardiac diseases, we integrated m6A epitranscriptome profiles from five cardiac pathological conditions (three drug-induced cardiac toxicity models-Evodiamine, Matrine, and TKI, hypertrophy, and heart calcification) and their control groups to construct the first predictive model for abnormal m6A modification in cardiac diseases. We constructed separate models for upregulated and downregulated modifications under different pathological conditions, performed feature selection and parameter optimization, and validated the performance of our models using an independent test set.

Results: m6AHD demonstrated excellent performance on the independent test set, with AUROC scores ranging from 0.728 to 0.880 across various pathological conditions. Cross-validation across different conditions and model interpretability demonstrated that m6A modifications exhibit similar patterns under different pathological conditions and are potentially regulated by similar factors, providing new clues for identifying targets in cardiovascular diseases at the epitranscriptome level. Furthermore, we validated our findings using a zebrafish model of Evodiamine-induced cardiotoxicity. The experimental results revealed significant morphological defects and a broad downregulation of m6A methyltransferase complex components, confirming the involvement of aberrant m6A machinery in the pathology of cardiotoxicity.

Discussion: m6AHD is the first dedicated framework for predicting multi-condition cardiac m6A dysregulation. Our findings underscore the critical role of m6A homeostasis in cardiomyocyte function and demonstrate that aberrant methylation patterns can serve as reliable indicators of cardiac pathology. This framework provides a robust computational tool for identifying potential therapeutic targets at the epitranscriptome level for cardiovascular diseases.

Cancer stem cells (CSCs) constitute a subpopulation of malignant cells with self-renewal and differentiation capabilities that drive tumorigenicity, metabolic adaptability, immune evasion, and therapeutic resistance, key factors contributing to metastasis and poor clinical outcomes. While genetic drivers of tumorigenesis are well-characterized, the epigenetic machinery sustaining the CSC state remains complex. Long noncoding RNAs (lncRNAs) represent a vast yet poorly understood class of regulatory molecules that influence gene expression at epigenetic, transcriptional, and post-transcriptional levels. Emerging evidence indicates that lncRNAs play a crucial role in shaping tumor cell plasticity and stemness-associated phenotypes. In this mini-review, we summarize current findings on how lncRNAs regulate CSC biology. We categorize their mechanisms of action, ranging from chromatin remodeling to the modulation of mRNA and protein stability. Furthermore, we discuss how the advent of high-resolution omics, including bulk tissue, single-cell, and spatial transcriptomics studies, is revolutionizing the identification CSC-associated lncRNAs and contributing to the development of clinically relevant biomarkers. Finally, we explore advanced methodologies for manipulating lncRNA expression, assessing the challenges and opportunities of lncRNA-directed therapeutics as a novel strategy to dismantle tumor plasticity and overcome drug resistance.

X-rays (XR) are electromagnetic waves capable of inducing significant biological effects in living organisms. Although widely used in medicine and industry, the impact of low-dose XR exposure on human health remains insufficiently characterized. XR can generate direct and indirect DNA damage such as single- and double-strand breaks, base modifications, and DNA-protein crosslinks, leading to chromosomal alterations that disrupt cellular homeostasis and may contribute to disease development. Although previous studies have reported general increases in cytogenetic damage at low exposures, they seldom provide detailed descriptions of which chromosomes are most affected, which structural or numerical alterations predominate, or how frequently each alteration occurs. This study aimed to characterize the type and frequency of chromosomal alterations and the spectrum of genetic damage, including both clonal and non-clonal alterations, in human lymphocytes exposed in vitro to a low X-ray dose (94.33 mGy), using non-exposed samples as controls. Peripheral blood was collected from 12 healthy donors, and genetic damage was assessed using GTG-banding cytogenetics and the cytokinesis-block micronucleus assay. Irradiated samples exhibited a significantly higher frequency of chromosomal alterations and fragile sites compared with their respective controls (p ≤ 0.0093). Among numerical alterations, monosomies were the most frequent, with chromosomes 8 and 21 being the most commonly affected, detected in 50% of irradiated samples. Structural chromosomal alterations predominantly involved chromosomes 11, 16, and 17, while recurrent deletions included del(15)(q22) and del(16)(q12). Among heterochromatic variants, chtb(9)(q12) was the most frequent, and fra(9)(q12) represented the most prevalent fragile site. MN frequency increased significantly after irradiation (p = 0.0214), and women exhibited higher MN frequencies than men regardless of treatment (p = 0.0224). Overall, these findings indicate that low-dose XR exposure is associated with detectable chromosomal damage and underscore the relevance of biosafety practices and cytogenetic monitoring approaches in contexts involving XR exposure, even at doses traditionally considered safe.

Background: Long QT Syndrome (LQTS) is characterized by prolonged QT intervals on electrocardiogram, which may progress into life-threatening polymorphic ventricular tachycardia and sudden cardiac death. Variants in the KCNH2 gene have been associated with congenital LQTS, with thousands identified to date but very few clinically characterized.

Objectives: To describe the rare single nucleotide variant KCNH2 (NM_000238.4):c.1066C>T (p.Arg356Cys) associated with drug-induced QT prolongation and to assess its pathogenicity risk using in silico tools and protein structural modeling in accordance with American College of Medical Genetics and Genomics (ACMG) guidelines.

Methods: Next-generation sequencing was performed for a patient presenting with drug-induced QT prolongation who was found to carry the rare KCNH2 1066C>T variant. Thirteen established gene discovery computational tools were employed to analyze the variant in silico. Additionally, structural modeling of the variant's region within the wild-type protein was performed utilizing AlphaFold.

Results: The clinical phenotype associated with the KCNH2 1066C>T variant has not been previously described in literature, except in combination with a variant in the KCNQ1 gene. Computational analysis with a meta-predictor, REVEL, supported variant pathogenicity, while predictive modeling and AlphaMissense illustrated the uncertainty of structural impacts in a disordered region. Risk analysis of the variant performed utilizing ACMG guidelines and ClinGen criteria-specific recommendations resulted in an overall classification of "uncertain significance".

Conclusion: To our knowledge, this is the first study reporting a direct phenotype-to-genotype association between the KCNH2 1066C>T variant and drug-induced QT prolongation, supplemented by in silico analyses and ACMG-based variant risk stratification. Our study underscores the importance of recognizing genetic predisposition in drug-induced QT prolongation and motivate further investigation of KCNH2 variants within the N-linker region.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder. Despite established genetic causes, missed or late diagnosis remains common in familial cases. This study reports a familial case of TSC to highlight the diagnostic challenges and evaluate the clinical efficacy of everolimus in managing cutaneous and neurologic symptoms.

Case presentation: The patient presented with refractory seizures, facial angiofibromas, and intellectual disability. Sequencing analysis revealed a mutation in the TSC2 gene in both the patient and the mother: c.848 + 281 (IVS9) C > T. No mutation at this site was detected in the father. Following the diagnosis, the patient received treatment with everolimus. A significant reduction in seizure frequency and improvement in facial angiofibromas were observed during the follow-up period.

Conclusion: A heterozygous splicing mutation in the TSC2 gene was identified, confirming the diagnosis of familial TSC. This case underscores the importance of genetic testing in suspected cases to prevent late diagnosis. Furthermore, our findings support the effectiveness of everolimus as a therapeutic option for alleviating TSC-associated neurological and cutaneous manifestations.

Endogenous, or 'self', vs. microbial, or 'non-self', RNA sensing can tip the scales between immune pathology and effective immunity. Cells are equipped to sense RNA, fundamental to trigger an innate immune response to clear viral infection that should not generate a harmful immune response against endogenous RNA. Multiple chemical modifications in RNA fine-tune its cellular sensing and are exploited by pathogens to evade immunity. Likewise, perturbations triggering self RNA sensing cause immune pathologies. This underscores the clinical need for a better understanding of self RNA recognition. Here, we address nucleic acid sensing in the innate immune response from an RNA-centric view. We discuss how self RNA is shielded from sensing by chemical modifications and subcellular compartmentalization, possible mechanisms and consequences of self-RNA sensing, and how this knowledge has been harnessed to revolutionize vaccine development.

Glaucoma, a leading cause of irreversible blindness, is a complex polygenic disease where significant clinical and genetic heterogeneity do not explain all glaucoma cases, highlighting the need for a deeper understanding of molecular mechanisms like epigenetics. This review examines the emerging role of key epigenetic mechanisms, specifically DNA methylation, histone modifications, and non-coding RNAs in glaucoma pathogenesis and their potential as biomarkers and therapeutic targets. We discuss how aberrant DNA methylation (e.g., GDF7 hypomethylation/CDKN2B hypermethylation) promotes trabecular meshwork fibrosis and increases optic nerve vulnerability, contributing to disease development and/or progression. The METTL23 histone methylation linked to retinal ganglion cell death at normal eye pressure, and disease-specific microRNA profiles further support the role of epigenetic involvement in glaucoma. The proof-of-concept studies of GDF7 neutralization in primate models and the OSK-factor reprogramming in aged and glaucoma mice models, show that epigenetic changes are reversible and can restore visual functions. DNA methylation-based epigenetic clocks identify glaucoma as an accelerated molecular aging process. Although promising, the current evidences are largely preclinical and long-term human data are still lacking. Nonetheless, the inherent reversible nature of epigenetics offers significant translational potential. Methylation, epigenetic clocks, and circulating microRNA profiles could enable early, non-invasive biomarkers for diagnosis and prognosis. Future efforts are needed to validate biomarkers in large cohorts and develop targeted epigenetic therapies. In conclusion, epigenetics is redefining our current understanding of glaucoma from a pressure-based disease to a modifiable link between genes and environment paving the way for personalized care for vision preservation beyond pressure-lowering treatments.

APOE is among the most extensively studied genetic loci in research on aging, morbidity, and mortality. Despite its well-established biological roles, empirical findings on the association between APOE and mortality remain inconsistent across studies. This heterogeneity is often attributed to biological complexity. In this Perspective, we argue that much of the apparent inconsistency instead reflects differences in modeling choices, variable definitions, and reporting practices, resulting in limited reproducibility and comparability. We highlight how pleiotropy, age-dependent effects, and selective survival make APOE particularly sensitive to analytical decisions. We focus on three underappreciated sources of irreproducibility: selective exclusion of rare APOE genotypes, lack of standardized baseline models, and routine adjustment for variables that are not confounders under Mendelian inheritance. We argue that all observed APOE genotypes should be included in primary analyses, that parsimonious baseline models adjusted only for variables independent of genotype should always be reported, and that overadjustment can obscure rather than clarify genetic effects. We propose a set of conceptual principles to improve reproducibility in studies of APOE, morbidity, and mortality, with implications for genetic epidemiology more broadly.

Introduction: Brain metastases (BMs) represent most malignant lesions of the central nervous system. Lung cancer-particularly lung adenocarcinoma (LUAD, ∼25%)-is the most common source of BMs. MicroRNAs (miRNAs) play a crucial role in regulating gene expression, thereby contributing to tumor progression and metastatic spread. Identifying these regulatory molecules may enable a deeper understanding of the mechanisms driving LUAD brain metastasis (LUAD-BM) development and reveal therapeutic targets to prevent or limit disease progression.

Methods: Next-generation RNA sequencing (RNA-seq) was performed on six LUAD-BM and six non-tumorous human brain tissue samples to assess miRNA expression profiles. Additionally, RNA-seq data from 20 primary LUAD and 15 normal lung tissue samples were obtained from The Cancer Genome Atlas (TCGA) database. MiRNAs showing the most pronounced alterations in LUAD-BM samples were selected for validation by real time quantitative polymerase chain reaction (RT-qPCR).

Results: Analysis of RNA-seq data identified 229 differentially expressed (DE) miRNAs between LUAD-BM and control samples. Functional annotation analysis indicated that these DE miRNAs are key regulators of tumorigenesis and metastasis. Using the Mann-Whitney U test, ten miRNAs were confirmed to differ significantly between LUAD-BM and normal brain tissue. Receiver operating characteristic (ROC) curve analysis demonstrated their diagnostic potential. Among the ten validated miRNAs, miR-200c-3p, miR-146b-5p, and miR-3934-5p showed distinct expression patterns between primary LUAD and LUAD-BM, while miR-10a-5p, miR-210-3p, and miR-130b-3p exhibited stepwise dysregulation along the normal lung-LUAD-LUAD-BM axis, suggesting their involvement in metastatic progression.

Conclusion: We identified ten miRNAs that showed preliminary ability to differentiate LUAD-BM from normal brain tissue. These findings indicate possible diagnostic and therapeutic implications. Among these, six miRNAs showed significant expression changes along the normal control-primary LUAD-LUAD-BM axis, highlighting their potential as biomarkers and therapeutic targets in BM development.

Young leaf color is a crucial agronomic trait in eggplant (Solanum melongena L.) significantly influencing photosynthetic efficiency, stress resistance, fruit quality, and ornamental value. However, research focusing on this trait remains relatively scarce. In this study, an F₂ (EP02×EP01) segregating population (n = 646) was developed from a cross between the purple young-leaved line EP02 and green young-leaved line EP01. Phenotypic characterization of the F₂ population revealed that the segregation ratio of green, purple-green, and purple phenotypes conformed to the expected 1:2:1 Mendelian ratio (χ² = 3.40, P > 0.05), indicating that the young leaf color trait in eggplant is controlled by a single incompletely dominant gene. To identify candidate loci associated with young leaf color, 30 individuals with extreme purple phenotypes and 30 individuals with extreme green phenotypes were selected from the F₂ population to establish two DNA bulks, namely, the purple trait bulk (ZS-pool) and the green trait bulk (LS-pool), respectively. Bulked Segregant Analysis (BSA) combined with whole-genome resequencing was performed on the two parental lines (EP02 and EP01) and the two bulks (ZS-pool and LS-pool). A total of 1,416,609 high-quality single nucleotide polymorphisms (SNPs) were generated and used for quantitative trait locus (QTL) mapping. Using the SNP-index method and Euclidean Distance (ED) analysis, a single QTL associated with young leaf color was identified on chromosome 10, covering a physical interval of 17.49 Mb (59,315,357-76,806,837 bp). Integrated analysis of SNP indices, ED values, and gene functional annotations suggested that Smechr1002213, Smechr1001752, and Smechr1001815 might be the candidate gene regulating young leaf color formation in eggplant. The findings of this study will lay a foundation for gene isolation and the elucidation of the genetic mechanisms underlying young leaf coloration in eggplant.