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.

Keywords: cancer; congenital developmental abnormality; three‐dimensional genome; topologically associating domain.

FIGURE 1

Chromosome 3D structure. In mammalian cells, chromosomes nonrandomly occupy specific regions within the interphase nucleus, known as chromosome territory (CT). Chromosomes can be classified into euchromatin and heterochromatin based on their transcriptional activity and regulatory roles. Euchromatin contains numerous transcriptionally active genes and is loosely arranged, while heterochromatin is tightly organized and primarily comprises transcriptionally silent genes. Heterochromatin at the nuclear periphery interacts with nuclear lamins, giving rise to Lamin‐associated domains (LADs). At the megabase level, the A/B compartment is further subdivided into TAD. Covering approximately 90% of chromatin structure, TAD represents the basic unit of 3D genome function and structure. Within TAD, high‐frequency interactions between enhancers and promoters regulate cell‐specific expression of developmental genes. CTCF, located at TAD boundaries, effectively isolates aberrant regulatory information interference and ensures smooth transcription.

FIGURE 2

Mechanism of loop extrusion. Cohesin acts as a molecular motor in the “loop extrusion” model: After binding to chromosomes, cohesin moves in two opposite directions along chromatin fibers and extrudes DNA loops until it contacts the target CTCF site in the converging direction. During TAD formation, cohesin undergoes functional changes by interacting with various regulatory factors. The cohesin loading factor, NIPBL, loads cohesin at specific DNA sites and facilitates cohesin's translocation on chromosomal fibers. Cohesin's release from chromosomes requires the PDS5 subunit to recruit the cohesin‐releasing factor, WAPL. The unloading efficiency of WAPL is stronger than that of PDS5, and both participate in the cohesin release process. Finally, cohesin ensures its smooth arrival at the target CTCF site through direct interaction with CTCF.

FIGURE 3

Mechanisms of enhancer–promoter interactions. Within TADs, cis‐regulatory elements play crucial roles in gene expression. Cohesin compresses DNA to form chromatin loops, thereby shortening the distance between enhancers and promoters. The promoter is the transcription start site for mammalian gene expression, determining the location and direction of transcription. The core promoter is a DNA sequence situated approximately 50 bp upstream and downstream of the transcription start site, containing multiple general transcription factor binding sites, and represents the minimal sequence required for initiating gene expression. Enhancers are significant non‐coding elements, typically located in nucleosome‐depleted regions, and contain multiple transcription factor binding sites.

FIGURE 4

Structural variation located between TAD. (A) Sequence deletions or duplications within TADs primarily affect regulatory functions by altering the number of enhancers and causing abnormal expression of target genes. (B) Sequence deletions at the boundaries result in the merging of adjacent TADs into one, forming a new TAD, referred to as “TAD fusion.” Duplication of DNA sequences containing boundary elements can create a “neo‐TAD.” The “neo‐TAD” is situated between the original TADs, wherein the interacting enhancers and promoters originate from different initial TADs, and their interactions do not interfere with the enhancer–promoter interactions within the original TADs. Chromosomal inversions occurring between adjacent TADs alter the position and/or orientation of DNA segments, placing genes and/or regulatory elements in different chromosomal contexts, and causing pathological effects known as “TAD shuffling”.