High powered microscopy has been enabling researchers to get a look at some of life’s most basic processes. Now, scientists have constructed simulations of chromosomes being packaged into condensed structures, which happens just before cells divide. The work, by Howard Hughes Medical Investigators, has been reported in Science.
“This is the most fundamental process of genetics,” said study coauthor and Howard Hughes Medical Institute (HHMI) Investigator Job Dekker. Chromosomes can break when genomic packing goes awry, and it's a hallmark of cancer.
Scientists first observed chromosomes under a microscope over a century ago, and Dekker noted that this work solves a mystery going back that far. Chromosomes exist as tangled masses in the nucleus; Dekker likened them to little blobs. When cells prepare to divide into daughter cells, chromosomes coil up, jamming about six feet of DNA into microscopic packages. After being sent to the daughter cells, the chromosomes can relax again.
Investigators have long known how chromosomes were structured, and several years ago, Dekker and colleagues found that tightly packed chromosomes were arrayed as consecutive loops. The transition between those states and the speed with which it occurs was a question. “The whole process happens in 10 to 15 minutes,” said Dekker. “It’s unbelievable.” The finding was controversial; some researchers thought chromosome are twisted into helices.
Dekker, and a team that included William Earnshaw of the University of Edinburgh’s Wellcome Trust Centre for Cell Biology and Leonid Mirny of the Massachusetts Institute of Technology synchronized chicken cells; all of them started packing chromosomes simultaneously. Then they took snapshots of the chromosomes at various time points.
The team fixed the chromosomes in place and looked at the DNA sequence where strands touched. That revealed clues about the architecture, which the team combined with computer simulations. The researchers were then able to predict how chromosomes make the change from a blob to a rod. “Because the structures are so totally different, you think, ‘Oh my, that must be a highly complicated and difficult process,’” Dekker said.
The packing strategy is efficient, which may show how cells can repeat the process over and over, Dekker noted. Chromosomes get pushed through small protein motors, ring-like structures called condensins, to form loops. Condensin II then weaves them into wide loops, while condensin I splits big loops into small ones. Hundreds of these loops then get twisted into spirals.
The new work also unifies what seemed to be conflicting views of mitotic chromosomes. They can be arranged in loops, but they can be helical as well, Dekker said. “I find this extremely satisfying,” he said. “I always aim for consilience. If you’re confronted with datasets that supposedly tell you two different things, can you find a way for them both to be right?”