Regulation of 3D Organization and Its Role in Cancer Biology

Abstract

Three-dimensional (3D) genomics is the frontier field in the post-genomics era, its foremost content is the relationship between chromatin spatial conformation and regulation of gene transcription. Cancer biology is a complex system resulting from genetic alterations in key tumor oncogenes and suppressor genes for cell proliferation, DNA replication, cell differentiation, and homeostatic functions. Although scientific research in recent decades has revealed how the genome sequence is mutated in many cancers, high-order chromosomal structures involved in the development and fate of cancer cells represent a crucial but rarely explored aspect of cancer genomics. Hence, dissection of the 3D genome conformation of cancer helps understand the unique epigenetic patterns and gene regulation processes that distinguish cancer biology from normal physiological states. In recent years, research in tumor 3D genomics has grown quickly. With the rapid progress of 3D genomics technology, we can now better determine the relationship between cancer pathogenesis and the chromatin structure of cancer cells. It is becoming increasingly explicit that changes in 3D chromatin structure play a vital role in controlling oncogene transcription. This review focuses on the relationships between tumor gene expression regulation, tumor 3D chromatin structure, and cancer phenotypic plasticity. Furthermore, based on the functional consequences of spatial disorganization in the cancer genome, we look forward to the clinical application prospects of 3D genomic biomarkers.

Keywords: cancer; chromatin; oncogene; spatial structure; super-enhancer.

FIGURE 1

A schematic diagram of multi-omics analysis between normal cells (control) and tumor cells. Hi-C data showed that tumor chromosome territories could be partitioned into A (active, red) and B (inactive, blue) compartments, chromatin is folded into topologically associating domains (TADs) (100–1,000 kb), and enhancer–promoter loops (10–500 kb); ChIP-seq revealed tumor genome-wide epigenetic changes, such as histone modifications; ATAC-seq detects tumor genomic chromatin accessibility using Tn5 transposase-specific recognition cleavage of open chromatin; whole-genome sequencing (WGS) detects tumor chromatin structural variations, including copy number variations (CNVs); genome-wide detection of tumor-specific genes by RNA-seq. Multi-omics reveals the hierarchical structures of 3D genome organization, transcription regulation, and structure variation mechanisms of the whole tumor genome at the genetic, epigenetic, and RNA levels.

FIGURE 2

Active chromatin hubs of tumor nuclear morphology and potential anticancer targets. Left: The internal structure of chromatin loop formed by spatial contacts in CTCF binding sites. Middle: Multiple proteins containing transcription factors (TFs) recruit mediators and RNA polymerase II (RNA Pol II) participates in nuclear transcription via different mechanisms. Small-molecule inhibitors exert anticancer effects by targeting tumor-promoting proteins or histone modifications. Right: Spatial dimension of SE-associated gene regulation in a gene-specific manner, transcription factor (TFs) binding to super-enhancers (SE) facilitates interaction with promoters with large genomic distances.