Music of the Genes Rises from the Cell Cycle

Changes in genome organization that accompany shifts in chromosomal conformation during the cell cycle may have epigenetic significance, report scientists who have tracked the movements of DNA loops by combining single-cell Hi-C technology and statistical analyses. This image was generated by a computer model of the folded DNA chromosomes from a single cell. [Csilla Varnai, Ph.D./Babraham Institute]

Echoing ancient notions, scientists are suggesting that complex movements in loops of chromatin are not just regular but also, potentially, meaningful. Whereas the ancients referred to the music of the spheres, the unheard harmonies of celestial bodies, scientists based at the Babraham Institute and the Weizmann Institute considered how gene expression could be affected by chromatin organization, which varies through the cell cycle. Essentially, the scientists—focused on genes rather than planets—are looking for meaningful, even beautiful, shifts in proportions.

The scientists, led by Babraham’s Peter Fraser, Ph.D., and Weizmann’s Amos Tanay, Ph.D., used single-cell Hi-C (high-resolution chromosome conformation capture) analysis to study chromosome conformations in thousands of individual cells. More plainly, they examined the organization of genes in over 4000 stem cells taken from mice, revealing patterns hardly less surprising than the retrograde motions of planets. These patterns, the scientists noted, consisted of a continuum of cis-interaction profiles that finely position individual cells along the cell cycle.

Details of this work appeared July 5 in the journal Nature, in an article entitled “Cell-Cycle Dynamics of Chromosomal Organization at Single-Cell Resolution.”

“We show that chromosomal compartments, topological-associated domains (TADs), contact insulation and long-range loops, all defined by bulk Hi-C maps, are governed by distinct cell-cycle dynamics,” the article’s authors wrote. “In particular, DNA replication correlates with a build-up of compartments and a reduction in TAD insulation, while loops are generally stable from G1 to S and G2 phase.”

Contrary to expectations, this study reveals that each gene doesn't have an ideal location in the cell nucleus. Instead, genes are always on the move, riding loops of chromatin that trace changing trajectories.

Scientists had believed that the location of genes in cells are relatively fixed with each gene having its rightful place. Different types of cells could organize their genes in different ways, but genes weren't thought to move around much except when cells divide. This is the first time that gene organization in individual cells has been studied in detail. The results provide snapshots of gene organization, with each cell arranging genes in unique ways.

“We've never had access to this level of information about how genes are organized before,” said Takashi Nagano, Ph.D., a senior research scientist at Babraham and a lead author of the current study. “Being able to compare between thousands of individual cells is an extremely powerful tool and adds an important dimension to our understanding of how cells position their genes.”

Collecting hundreds of thousands of pieces of information about gene positions from just one cell is a significant challenge and it has relied on single-cell HiC technology pioneered by Nagano and colleagues in 2013. Combining this technology with statistical analyses performed by Tanay's team has made this detailed research possible. A version of the Hi-C technique was also recently shown to have the potential to improve cancer diagnoses.

“We typically see that changes to gene activity have a great impact on health, disease, and evolution,” commented Fraser. “It's now obvious that genome organization may have a part to play in this, and our research shows that the effects of location on genes may be a constantly moving target. Understanding how the genome is controlled during this constant reshuffling is an important step toward understanding how our genomes and genes affect our lives.”

“Chromosomes in proliferating metazoan cells undergo marked structural metamorphoses every cell cycle, alternating between highly condensed mitotic structures that facilitate chromosome segregation, and decondensed interphase structures that accommodate transcription, gene silencing, and DNA replication,” explained the authors of the Nature paper. “Whole-genome three-dimensional structural models reveal a radial architecture of chromosomal compartments with distinct epigenomic signatures. Our single-cell data therefore allow re-interpretation of chromosome conformation maps through the prism of the cell cycle.”