Three‐dimensional genome structure and function

Abstract

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.

Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G)

“…In fact, atRAinduced remodeling of presumptive three-dimensional chromatin loops has previously been reported for RA-regulated genes, including CASP9 and CYP26A1 [33]. Correlations between extracellular stimulation-promoted changes in gene expression and topological changes in those genes have been observed for other nuclear receptors [34][35][36][37] and are in agreement with the general observation that gene expression and chromosome architecture are closely interdependent and influence each other, especially in the case of long-distance enhancers [32,38]. Elucidating the roles of atRA-induced changes in RAI1 expression during early brain development and in the mature brain remains an important goal for subsequent studies.…”

Enhancers dysfunction in the 3D genome of cancer cells

“…Cancer-associated SVs can disrupt the physiological 3D genome structure by causing A/B compartments switching (Dubois et al, 2022)or TAD reorganization (shuffling, fusion or neo-formation) (Lupiáñez et al, 2015;San Martin et al, 2021;Xu Z. et al, 2022), resulting in the ectopic activation of oncogenes or inhibition of tumor-suppressing genes (Liu et al, 2023). That is the case for several primary and metastatic prostate cancer cell lines, where SVsmediated DNA loci transition from the inactive to active compartment and vice versa can cause the fusion of TMPRSS2-ERG genesa marker used for prostate cancer malignancy stratification - (San Martin et al, 2021), and the activation of numerous genes linked to carcinogenesis (i.e., WNT5, TMPRS, and CDK44) (San Martin et al, 2021) (Table 1).…”