3D genome organization in health and disease: emerging opportunities in cancer translational medicine

Abstract

Organizing the DNA to fit inside a spatially constrained nucleus is a challenging problem that has attracted the attention of scientists across all disciplines of science. Increasing evidence has demonstrated the importance of genome geometry in several cellular contexts that affect human health. Among several approaches, the application of sequencing technologies has substantially increased our understanding of this intricate organization, also known as chromatin interactions. These structures are involved in transcriptional control of gene expression by connecting distal regulatory elements with their target genes and regulating co-transcriptional splicing. In addition, chromatin interactions play pivotal roles in the organization of the genome, the formation of structural variants, recombination, DNA replication and cell division. Mutations in factors that regulate chromatin interactions lead to the development of pathological conditions, for example, cancer. In this review, we discuss key findings that have shed light on the importance of these structures in the context of cancers, and highlight the applicability of chromatin interactions as potential biomarkers in molecular medicine as well as therapeutic implications of chromatin interactions.

Keywords: 3D genome organization; ChIA-PET; biomarkers; cancer; chromatin interactions; translational medicine.

Figure 1.

The 3-Dimensional chromatin architecture of the cell. The fundamental organizational unit of chromatin are the nucleosomes, which are approximately 147 bp, which makes up the 10 nm “beads on a string” structure seen by Electron Microscopy (EM). chromatin interactions, in the form of duplex interactions in which 2 loci come together, or complex interactions in which more than 2 loci interact with each other, further organize chromatin at the kilobase level. Megabase-sized Topologically Associating Domains (TADs) further organize chromatin, and finally, chromosomes occupy distinct “chromosome territories” in cell nuclei.

Figure 2.

Chromatin conformation structure analysis methods. The “C” methods take advantage of proximity ligation, whereby interacting chromatin regions stabilized by cross-linking cell fixation are ligated, and the ligation products are deconvoluted by PCR, next-generation sequencing or other methods. FISH is a microscopy-based method that uses differently-labeled Bacterial Artificial Chromosomes (BACs) to detect genomic regions in close proximity.

Figure 3.

Mechanisms by which aberrant chromatin conformation structures may result in diseases such as cancer. These mechanisms include: (1) Regulation of transcriptional and epigenetic changes by chromatin interactions, including aberrant methylation and dysregulation of transcription. Aberrant chromatin interactions could lead to altered long non-coding RNA (lncRNA) and mRNA levels. In addition, aberrant chromatin interactions could lead to dysregulated co-transcriptional splicing, and loss of gene co-regulation, thus resulting in cancer. Epigenetic factors and long non-coding RNA may control chromatin interactions. (3) DNA replication. Early and late replicating origins of replication have been found to cluster together through chromatin interactions. Dysregulation of chromatin interactions could interfere with the organization of DNA replication, leading to aberrant DNA replication and consequent cancer formation. (3) Structural variants and recombination, whereby DNA breaks and repair at chromatin interactions can facilitate the formation of translocations and fusion genes, thus resulting in cancer. The formation of translocations, deletions or insertions and other structural variants could also lead to the formation or disruption of chromatin interactions. Genome organization may also facilitate virus and transposon integration at particular locations in the genome.