An international group of researchers from the Crick, Imperial College London, Waseda University and the Cancer Institute of the Japanese Foundation for Cancer Research have redrawn the idea of chromosome shape, finding that they’re not always stable X-shaped structures but are constantly in flux as cell division takes place.

A mixture of DNA and proteins – known as ‘chromatin’ – sits inside every cell nucleus as a jumbled puddle of genetic information. As cells prepare to divide during mitosis, the chromatin is condensed into rod-shaped chromosomes, allowing the cell to neatly split its genetic material between two new cells.

Researchers including the Crick’s Frank Uhlmann have sought to explain a strange phenomenon that occurs during mitosis: chromosomes begin as long threads of universal width, but then continuously shorten and thicken. His team’s latest work, published in EMBO Reports, outlines a mechanism for this dynamic shape change.

“The chromosome shape is determined by a protein complex called condensin, which helps fold and compact the DNA,” explains Frank. “There are debates among scientists and different models proposed as to how this happens, whether loops of DNA are actively extruded by condensin, or whether these protein complexes capture chance encounters between DNA strands.”

Changing shapes

Frank worked with Toru Hirota and Yoshi Kusano at the Cancer Institute of the Japanese Foundation for Cancer Research in Tokyo to live-image chromosomes in the lab over time. They observed that, as the cells entered mitosis, distinct chromosomes formed in around 12 minutes, and these became shorter and thicker by the 20-minute mark. When they paused the cell from completing cell division, many chromosomes continued to get shorter and thicker until the end of the recording after six hours.

Yasu Kakui, a former researcher in Frank’s lab and now a professor at Waseda University in Tokyo, joined the team to measure chromosome arm lengths and widths at various time points.

“We recorded that the shortest arms shrank rapidly in the first 30 minutes and then maintained a relatively constant shape,” says Yasu. “But the longest arms continued to shorten and thicken until the end of the experiment. This suggested that short chromosome arms reach a final state relatively quickly, before the next stage of cell division begins, but long chromosomes might not reach this steady state.”

By measuring the dimensions of the arms, the team concluded that chromosomes are aiming for a ‘final roundness’ – a ratio that’s the most physically stable.

“It was fascinating seeing that the chromosomes were in constant flux,” says Frank. “They continued to get shorter and thicker, suggesting that there’s a steady state they’re aiming to reach.”

Capturing DNA to achieve a steady state

To make sense of Yasu’s measurements, the researchers worked with physicist Bhavin Khatri, visiting scientist at the Crick and research fellow at Imperial College London, together with Imperial undergraduate student Maya Lopez to produce computer simulations of the shape changes.

“These relatively simple simulations captured what the team had seen in the lab,” says Bhavin. “Longer chains take far longer to reach a stable length, suggesting they aren’t in a steady state at cell division, whereas shorter chains reached a steady state almost straight away.”

The simulations supported the theory that the loop capture mechanism explains how condensin forms chromosomes. Modelling the chance capture of DNA strands resulted in similar shapes as seen in the lab, suggesting this is the way condensin helps chromosomes work towards a steady state. 

A state that’s unachievable for most

For Frank, the results of these multidisciplinary experiments portray chromosomes in a fresh light. 

“They’re so much more dynamic than the textbook X-shape suggests,” he says. “We’ve shown that the length of time chromosomes spend in mitosis dictates whether they will all reach a final shape or not, and that capturing DNA strands by chance aids in this process. It’s interesting to think that the majority of chromosomes will keep trying to reach this stable oval shape, but will never get there."