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Linear DNA undergoes a series of compression and folding events, forming various three‐dimensional (3D) structural units in mammalian cells, including chromosomal territory, compartment, topologically associating domain, and chromatin loop. These structures play crucial roles in regulating gene expression, cell differentiation, and disease progression. Deciphering the principles underlying 3D genome folding and the molecular mechanisms governing cell fate determination remains a challenge. With advancements in high‐throughput sequencing and imaging techniques, the hierarchical organization and functional roles of higher‐order chromatin structures have been gradually illuminated. This review systematically discussed the structural hierarchy of the 3D genome, the effects and mechanisms of cis‐regulatory elements interaction in the 3D genome for regulating spatiotemporally specific gene expression, the roles and mechanisms of dynamic changes in 3D chromatin conformation during embryonic development, and the pathological mechanisms of diseases such as congenital developmental abnormalities and cancer, which are attributed to alterations in 3D genome organization and aberrations in key structural proteins. Finally, prospects were made for the research about 3D genome structure, function, and genetic intervention, and the roles in disease development, prevention, and treatment, which may offer some clues for precise diagnosis and treatment of related diseases.

IntroductionAlzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder that primarily affects older individuals. N7-methylguanosine (m7G) is a common RNA chemical modification that impacts the development of numerous diseases. Thus, our work investigated m7G-related AD subtypes and established a predictive model.MethodsThe datasets for AD patients, including GSE33000 and GSE44770, were obtained from the Gene Expression Omnibus (GEO) database, which were derived from the prefrontal cortex of the brain. We performed differential analysis of m7G regulators and examined the immune signatures differences between AD and matched-normal samples. Consensus clustering was employed to identify AD subtypes based on m7G-related differentially expressed genes (DEGs), and immune signatures were explored among different clusters. Furthermore, we developed four machine learning models based on the expression profiles of m7G-related DEGs and identified five important genes from the optimal model. We evaluated the predictive power of the 5-gene-based model using an external AD dataset (GSE44770).ResultsA total of 15 genes related to m7G were found to be dysregulated in patients with AD compared to non-AD patients. This finding suggests that there are differences in immune characteristics between these two groups. Based on the differentially expressed m7G regulators, we categorized AD patients into two clusters and calculated the ESTIMATE score for each cluster. Cluster 2 exhibited a higher ImmuneScore than Cluster 1. We performed the receiver operating characteristic (ROC) analysis to compare the performance of four models, and we found that the Random Forest (RF) model had the highest AUC value of 1.000. Furthermore, we tested the predictive efficacy of a 5-gene-based RF model on an external AD dataset and obtained an AUC value of 0.968. The nomogram, calibration curve, and decision curve analysis (DCA) confirmed the accuracy of our model in predicting AD subtypes.ConclusionThe present study systematically examines the biological significance of m7G methylation modification in AD and investigates its association with immune infiltration characteristics. Furthermore, the study develops potential predictive models to assess the risk of m7G subtypes and the pathological outcomes of patients with AD, which can facilitate risk classification and clinical management of AD patients.