Moving on into a New Frontier: “3-dimensional genomics” (the way the chromosomes are situated in the nucleus)

As these GEITP pages keep harping on –– the factors that contribute to any trait (response to a drug or environmental toxicant, hair color, height, blood pressure, risk of type-2 diabetes, risk of autism spectrum disorder, etc.) include: genotype (DNA sequence); epigenetic effects (chromosomal but not DNA sequence changes); endogenous influences (renal blood flow, age, cardiovascular status, etc.); environmental factors (cigarette smoking, drug exposures, occupation, etc.); and even one’s individual microbiome differences (gut bacteria contributing metabolites). Now there appears to be a new kid on the block: “3D-genomics.”

It is becoming possible (technically) to evaluate how chromatin is organized in the 3-dimensional (3D) nuclear space (i.e. how the chromosomes are configured/oriented, relative to one another) –– which will help us understand various DNA-templated processes such as transcription, replication, and DNA recombination. This field has recently transitioned from microscopy-based approaches limited in resolution and throughput to a powerful combination of genomics, microscopy and computational technologies. Thus, the genomicist [see attached editorial] is now able to paint a high-resolution multi-scale picture of chromatin architecture. The breakthrough was spearheaded 16 years ago by development of the chromosome conformation capture (3C) method [Science 2oo2; 295, 1306]. Scientists then began to realize that chromosomes normally fold into active and inactive compartments, which are partitioned into smaller topologically-associating domains (TADs) and chromatin loops.

Intriguingly, genome topology is considered to have important roles in the regulation of gene expression, DNA replication, X-chromosome inactivation, adaptive immunity, and cell-fate decisions. Recent studies have shown that abnormal chromatin folding can lead to disease, including developmental disorders and cancer. Data generation, however, is still challenging and costly. Furthermore, it remains difficult to predict how complex changes to mammalian genomes (e.g. the large structural alterations often present in human disorders) impact chromatin architecture and subsequent gene regulatory processes. For those interested in reading further, please check out Nat Genet (May 2o18) 50: page 631 & pp 662–667. These articles introduce new methodologies that promise to further facilitate the generation, and functional interpretation, of genome-wide chromatin interaction maps.


Nature Genetics May 2o18; 50: pp 634–635 [Editorial]

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