Comparative and Functional Genomics最新文献

Epidermolysis bullosa (EB) is a genetically heterogeneous skin fragility disorder. Some subtypes also involve other organs, including the pulmonary, gastrointestinal, and renal systems. One severe form, junctional epidermolysis bullosa (JEB), is characterized by cleavage within the skin layers. The rarest and most lethal spectrum of this disorder includes pyloric atresia (PA), known as JEB-PA. The number of reported cases in Thailand is limited. Using trio whole exome sequencing, we identified a Thai newborn with lethal JEB-PA caused by novel null compound heterozygous variants in ITGB4. The patient carries a known nonsense variant (c.2533C>T) and a novel frameshift indel variant (c.1614delT) in ITGB4, inherited from her parents. Both are null variants that result in a premature termination codon (PTC). A comprehensive review of existing literature was conducted to gather information on disease-causing variants and genotype–phenotype correlations in JEB-PA. We summarized 50 previously reported JEB-PA cases, detailing disease severity and ITGB4 variants. We found that nonsense and frameshift indels were predominant in lethal cases (32/62 alleles), whereas missense variants were more common in nonlethal forms (18/38 alleles). Pathogenic variants were most frequently located in the Fibronectin II–like domain (FnIII) and cytoplasmic domain (CP) for null variants and in the von Willebrand factor Type A (VWFA) domain for missense variants. We emphasize the importance of genetic testing in these heterogeneous skin disorders. Molecular results reveal the disorder’s diagnosis, provide a precise prognosis, and guide the genetic counseling process for the family. Moreover, understanding pathomolecular mechanisms can lead to potential future treatments.

Background: Autophagy exerts a vital role in the development of atherosclerotic lesions. Mounting evidence suggests a significant link between autophagy and atherosclerosis.

Methods: Two atherosclerotic plaque datasets were integrated from the Gene Expression Omnibus (GEO) database. After differentially expressed genes (DEGs) were determined, enrichment analyses were subsequently performed on DEGs. We employed weighted gene coexpression network analysis (WGCNA) and cross-linked these modules with DEGs and autophagy-related genes. Subsequently, a prediction model was established for evaluation. RT-PCR was adopted to identify hub gene expression. The consensus clustering analysis on the overlapping genes was executed. Evaluation of immune infiltration was conducted on the merged dataset. A TF-miRNA-mRNA regulatory network was then established for the hub genes.

Results: The differential gene expression analysis uncovered 259 DEGs. Enrichment analysis showed that immune and inflammatory reactions were related to atherosclerosis. By intersecting DEGs, WGCNA module genes, and ARGs, 13 overlapping genes were obtained. Four machine learning models identified seven hub genes. Furthermore, six of the seven genes demonstrated potential for disease diagnosis. The prediction model, based on the expression levels of these six genes, yielded satisfactory results. RT-PCR analysis demonstrated that the mRNA expression of six genes meets expectations. Consensus clustering divides 13 overlapping genes into two clusters, C1 and C2, with significant differences in immune infiltration. Immune cell infiltration demonstrated heightened immune activity within the atherosclerotic plaque group. A TF-miRNA-mRNA regulatory network was established for the six genes.

Conclusion: It is anticipated that these six genes may serve as significant and valuable targets for future research into atherosclerosis.

Objectives: The purpose of this study was to investigate the role of the ITGB1/FAK/AKT pathway in NRG-1 in mediating the axonal growth of dorsal root ganglion neurons in Type I diabetic rats and to explore the mechanism of neuronal axonal regeneration.

Result: The effects of NRG-1 on neurite outgrowth in diabetic rats were determined by protein quantification and axon length analysis in which axons were identified with tubulin-βIII-specific staining. Western blot showed that the signaling activity of the ITGB1/FAK/AKT pathway was decreased in diabetic rats compared with normal rats, and exogenous NRG-1 significantly promoted axonal growth and activated the pathway. After the addition of ITGB1-specific siRNA, the axonal growth–promoting effect of NRG-1 was partially reversed.

Conclusion: NRG-1 promotes axonal outgrowth in diabetic DRGs via upregulating the ITGB1/FAK/AKT pathway, providing a potential target for diabetic neuropathy.

Plant-specific transcription factors known as WUSCHEL-related homeobox (WOX) proteins are crucial for regulating plant development and responses to stress. This study represents the first thorough characterization of the WOX gene family in quinoa (Chenopodium quinoa, CqWOXs). In total, we identified 13 probable CqWOX genes, which were categorized into three main subgroups (ancient subgroup, intermediate subgroup, and WUS subgroup) based on phylogenetic analysis. Synteny analysis revealed 12 CqWOX genes as orthologs of WOX genes in Beta vulgaris, Amaranthus hypochondriacus, and Spinacia oleracea, while 10 orthologs were found in Arabidopsis thaliana. Five segmentally duplicated WOX gene pairs were identified in the quinoa genome, all of which have undergone purifying selection, as indicated by their Ka/Ks values being less than one. Additionally, the 2.0 kb promoter regions of CqWOXs were found to harbor various cis-acting elements related to hormone-responsiveness, stress-responsiveness, growth and development, and light-responsiveness elements. The protein–protein interaction network established included 6 Arabidopsis WOX proteins and 10 other notable proteins that showed strong interactions with WOX proteins, comprising 16 nodes in total. Transcriptome analysis demonstrated that CqWOX genes in quinoa exhibit both tissue-specific and salt-responsive expressions. Several genes were repressed in salt bladders, while others showed increased expression, suggesting their potential roles in stress adaptation. Expression profiles differed in leaf and root tissues under salt stress conditions. This study suggested that CqWOX genes exhibit unique characteristics that may facilitate further investigation in future research.

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer mortality, with limited treatment options due to its high heterogeneity. SPP1⁺ tumor-associated macrophages are emerging as key regulators of the tumor immune microenvironment and disease progression.

Methods: We integrated scRNA-seq data from the GEO database with bulk transcriptomic data from TCGA and ICGC. Immune cell subsets were identified through clustering and ligand–receptor interaction analyses. Prognostic genes associated with SPP1⁺ macrophages were screened using univariate Cox and Lasso regression. A risk model was built and validated using survival analysis and ROC curves. A multialgorithm AI framework was applied to enhance model performance.

Results: Twelve immune cell types were identified, with SPP1⁺ macrophages showing strong interactions with tumor and immune cells. A seven-gene signature (SNX5, YBX1, GNPD1, RAB32, TPM3, ATP6V0B, and RAB7A) was constructed, effectively stratifying patients by survival risk in both TCGA and ICGC cohorts. The model showed strong predictive power with high AUC values and a significant correlation between gene expression and risk scores.

Conclusion: SPP1⁺ macrophages play a crucial role in HCC immune modulation and progression. The gene signature developed provides a reliable tool for prognosis and may inform personalized treatment. This SPP1⁺ macro-associated signature offers a novel and robust biomarker for prognosis and may guide precision immunotherapy strategies in HCC.

Objective: This study is aimed at exploring disease progression–associated genes from platelet-derived genes and at investigating their underlying roles in prognostic outcomes in lung cancer.

Methods: Platelet RNA sequencing (RNA-seq) from healthy controls (n = 81) and lung cancer patients at early (n = 102) and advanced stages (n = 65) was conducted, and the genes from which that continuously changed with disease progression were screened by differential analysis and WGCNA. RNA-seq and survival data of LUAD cohort from TCGA database was utilized for prognostic investigation. GSE31210 and GSE18842 datasets from GEO database were utilized for validation of gene expression and prognosis. The immunedeconv package and ESTIMATE algorithm were employed for investigation of immune status. Gene mutation was evaluated based on the cBioPortal database. Drug sensitivity was assessed based on the GDSC database.

Results: Totally, 53 platelet-derived genes that were persistently dysregulated along with the progression from normal to early and then advanced were identified. These 53 genes were primarily enriched in ribosome biogenesis–related functions. Five prognostic genes, including HPSE, DENND1C, GRWD1, HLA-DQA1, and PDXK, were identified to further develop a risk signature, which exhibited moderate power for forecasting the prognosis of lung cancer patients in training, testing, and validation sets. In addition, a high-risk signature score was linked to low infiltrating levels of most immune cells and a high tumor purity in the tumor microenvironment, as well as low IC50 values to several common chemotherapeutics, such as docetaxel, gefitinib, and erlotinib. Moreover, energy metabolism and proliferation-related pathways were activated, while immune-related pathways were inactivated in the high-risk group. Among the five prognostic genes, HLA-DQA1 harbored a relatively higher alteration frequency in LUAD (3%, alteration type: amplification).

Conclusion: The five platelet-derived prognostic genes might be potential targets or biomarkers in lung cancer.

Background: MEDNIK syndrome is a rare copper metabolism disorder caused by AP1S1 variants. Herein, we report the clinical and genetic characteristics of MEDNIK syndrome in two siblings.

Methods: The clinical treatment process for MEDNIK syndrome and over 4 years of follow-up data were analysed in two siblings. Microscopic observations of the patients’ hair were conducted. Gene sequencing, three-dimensional structural reconstruction of protein sequences, and in vitro mRNA splicing experiments were performed.

Results: The proband and his sister exhibited developmental delays, seizures, yellow hair, sparse teeth and a high forehead. Furthermore, the sister initially presented with intractable diarrhoea and severe pneumonia. Both siblings showed varying degrees of developmental delays during follow-up, and the proband also showed symptoms of attention deficit hyperactivity disorder. The microscopic hair examination revealed a deficiency in intermediate pigment, a pale colour and an intermittent or absent medulla. Genetic sequencing revealed a homozygous AP1S1 mutation at the splicing site (NM_001283.3): c.430-1G>A. The in vitro mRNA splicing experiments confirmed a single base-pair deletion in the fifth exon of the mRNA sequence of the mutated plasmid, resulting in a frameshift mutation (p.Glu144ArgfsTer83). The mutation was inherited from both parents and classified as pathogenic according to the American College of Medical Genetics and Genomics guidelines, based on clinical features and family analysis.

Conclusion: Both children with MEDNIK syndrome exhibited heterogeneous clinical phenotypes. Sparse teeth may be a previously unnoticed feature of MEDNIK syndrome. The pathogenic c.430-1G>A homozygous variant enriches the mutation spectrum of AP1S1. This mutation causes a frameshift mutation in the protein, altering the protein structure and affecting protein function.

Background: Colon adenocarcinoma (COAD) is a common digestive malignancy with limited therapies and a poor prognosis. Previous studies have highlighted lncRNAs’ key role in cancer, but the exact function of lncRNA SNHG25 in COAD remains unclear.

Methods: In this study, we obtained COAD transcriptome data from the UCSC Xena database, screened for differentially expressed genes, and assessed the diagnostic efficacy of SNHG25 using the DESeq2 package. Subsequently, the SNHG25 high- and low-expression groups were enriched and analyzed for immune cell infiltration characteristics and correlation with SNHG25 using the CIBERSORT and ESTIMATE algorithms. Its impact on immunotherapy and drug sensitivity was assessed by combining TIDE with oncoPredict database. The target mRNAs were further screened by Encori platform and potential target drugs were predicted using molecular docking technology. Finally, qRT-PCR, CCK-8, wound healing, and transwell assays were used to assess the mRNA expression levels and potential biological functions of SNHG25.

Results: SNHG25 expression level was upregulated in COAD samples, and the ROC curve showed the area under curve (AUC) value = 0.937, revealing its strong diagnostic ability. Functional enrichment analysis showed that its high expression was associated with activation of oxidative phosphorylation pathway, while low expression was enriched in apoptosis and immune-related signaling pathways. Immune infiltration analysis showed that SNHG25 was significantly associated with a variety of immune cell subtypes (e.g., macrophages and neutrophils) and might be involved in the remodeling of the tumor immune microenvironment. ZMYND8 was identified as a key downstream mRNA target (AUC = 0.811), and three potential therapeutic drugs—demecolcine, piroxicam, and vorinostat—were predicted based on DSigDB screening and validated by molecular docking, with binding energies of −6.48, −7.15, and −5.39 kcal/mol, respectively. Finally, in vitro cellular assays confirmed that SNHG25 expression was elevated in COAD cell lines (p < 0.0001), and its knockdown significantly suppressed cell proliferation, migration, and invasion.

Conclusion: This study highlights that SNHG25 is highly expressed in COAD and promotes tumor progression through multiple mechanisms, advancing research and treatment strategies for this malignancy.