Organized ‘chaos’: The first map of inter-chromosomal interactions

Posted on November 20, 2024

Summary:

Research uncovers relationship between inter-chromosomal space and gene activity in genome topology maps.

Red and blue chromosomal arms swirl in a circle, with red, blue and black dots heavily concentrated on the far left and middle right sides of the circle.

A topological map of a ‘mock nucleus’ showing the space and proximity of chromosomes in the nucleus of a cell.

Scientists at The Hospital for Sick Children (SickKids) and the University of Toronto have generated a topological map of the human genome, shedding light on the role of inter-chromosomal interactions in this emerging field of genomic research.

Inside the control centre of every human cell, 23 pairs of chromosomes store genetic information, providing each cell with the instructions it needs to function. While progress in genome sequencing over the last 30 years has significantly advanced genomic research, scientists know little about how these chromosomes spatially interact and communicate with each other.

Now, the Maass lab has used a machine learning model to identify and analyze over 40,000 inter-chromosomal interactions across 53 cell types, published in Nature Communications.

“At first glance our chromosomes may resemble a plate of spaghetti – somehow a non-random mess of threads within our cells. Our research has made sense of the tangle and illuminated the highly organized structure of chromosomes and their contact points within a cell,” says Dr. Philipp Maass, Scientist in the Genetics & Genome Biology program.

A chromosome showing strands of DNA inside it.

Did you know?

Carl Rabl first proposed that chromosomes are arranged in a non-random way in 1885, with centromeres (the middle of the chromosome) near the edge of the cell nucleus, and telomeres (the ends of the chromosome) located away from the centromeres. This arrangement, called the Rabl orientation, has now been confirmed in human genomes by Maass’ team.

Building a compendium of ‘kissing chromosomes’

In 2019, Maass published a review on "kissing chromosomes" – chromosomes that come close and interact more often than others.

Kissing chromosomes in action

Did you know that your sense of smell is the result of hundreds of genes located on different chromosomes? Many of these are “kissing chromosomes” that interact closely together, resulting in the gene expression that allows you to follow your nose!

Building on this concept, the team has now discovered 61 specific regions in the genome, called "topological anchors," that consistently interact across different cell types. These anchors help organize the overall structure of the genome, ensuring that chromosomes are positioned correctly within the cell nucleus and do impact how genes work.

On the left, a green circle made of dots, concentrated on the far left of the circle. On the right, a circle of blue dots concentrated on the far left and right sides of the circle. — The study found that gene expression (green) and transcription factor binding (blue) within the cell nucleus overlapped with areas of higher inter-chromosomal activity shown in the topological map of a 'mock nucleus'.

“These interactions often happen in areas of the genome that are dense with genes and highly active in terms of gene expression,” says Maass, who holds a Canada Research Chair Tier 2 in Non-coding Disease Mechanisms. “What we found suggests that where and how often inter-chromosomal interactions take place can actually influence how our genes work and cells’ function.” The team further validated these findings across biological sex and found similarities in chromosomal structure across cell types.

Maass notes that the findings were made possible by the diverse and complementary research backgrounds on the team, spanning from industrial engineering to imaging experts.

A baseline for future chromosomal analysis

To date the research team has only mapped healthy cells, but are eager about the possibility of applying this new method to genomic data from patients with cancer and other health conditions. By comparing the chromosomal topology of healthy cells to re-organized genomes in diseased cells, the team hopes to uncover even more about how our genomes are organized and how they function – and identify new ways to classify and treat these conditions.

“By discovering the intricate details of genome topology, we as scientists are better equipped to tackle complex genetic questions, bringing us closer to advanced genetic therapies that can provide patients with truly individualized care,” says Maass.

This study was funded by Canada’s New Frontiers in Research Fund, the NSERC Discovery Grant and the Canadian Institutes of Health Research (CIHR).