After extract dilution (a technique that disperses individual chromosomes in a laboratory), chromosomes are shown. Credit: Pavan S. Choppakatla
The ability of cells to fit six feet of DNA in a 10-micron nucleus is crucial to human life. This is equivalent to fitting one mile of string into one green pea. However, stuffing genes into small spaces is only half of the battle. It is important that the DNA be organized and twisted into loops so that it remains easily accessible.
New research has revealed that linker histones are the proteins responsible for controlling whether DNA is made into long or thin chromosomes. They can be composed of small loops or large loops. These findings were published in eLife and are the first to show how linker histones affect chromosome shape at the molecular level.
Hironori Funabiki, Rockefeller's Hironori Funabiki, says that the linker histone used to be thought to only have an effect on a small range of genetic material. "We now know that the linker histone controls the number and shape of the loops in the chromosome, which is a larger regulation area than we expected.
Beyond "beads on strings"
The nucleosome is the center of genetic material. This is often depicted as a string with a length DNA "string" wrapped around a central protein "bead". A type of protein clipthe linkerhistone is used to clamp the string to its bead. This is responsible for folding many nucleosome beads intochromatin fibers. After being ratcheted by a molecular motor called the condensin that organizes chromatin into loops, these fibers become chromosomes.
There are many shapes and sizes of chromosomes, depending on how large each chromatin loop is. Funabiki illustrates this example by using the frustrating experience of coiling wired headphones. The headphones will fit easily into your pocket if you make many small loops. However, if you only wind the wires into a few large loops, your headphones will form a bulky mass. A greater number of small loops will result in shorter and thinner chromosomes. However, a smaller number of large loops of Chromin will produce thicker, longer chromosomes.
Scientists understood that loop formation was at the core of chromosome shape and size. However, it was a mystery how cells could tune this process to create larger loops or smaller loops.
Linker histone has a new role
Funabiki and his colleagues set out to solve the mystery. The University of Massachusetts Medical School developed a method to analyze DNA from frog eggs. It found that linker histones, beyond binding condensin to nucleosomes or forming chromatin loops, also prevent condensinfrom binding to them.
The picture of loop formation was emerging, with linker histones at its core. Researchers found that changing the shape of a cell's chromosome is as easy as increasing or decreasing the amount linker histone to inhibit condensin.
A high level of linker histone blocks condensin so that the protein complex can make fewer loops. Because only a few loops are being formed, there is enough slack for those loops develop into large coils which will eventually become chromosomes. Lower levels of linker histone trigger the opposite process. Condensin forms fewer loops and has less fiber to work with. This results in a lot of smaller loops that are compacted into thin, long chromosomes.
Funabiki suggests that cells might have developed the ability to adjust the length of chromosomes to increase or decrease their growth. He says that the longer the chromosome, the longer it takes for cells to split. Frog eggs are often exposed to hazardous environments so it is crucial that they hatch quickly. The speed at which the eggs turn into tadpoles or escape is crucial for successful reproduction. Frog eggs may have shorter chromosomes which allows for faster cell division.
Funabiki's lab plans to investigate whether linker histones can play similar roles in shaping the shape and size of human chromosomes in the future. Pavan S. Choppakatla (lead author) says that the initial work was limited to frog eggs. He is also a member in the Funabiki laboratory. To determine if our findings can be generalized, we are currently studying linker histones in somatic cells and human eggs.
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More information: Pavanchoppakatla and colleagues, Linker histone (H1.8) inhibits chromatin binding to condensins, and DNA topoisomerase (2) to tune chromosome size and individualization. eLife (2021). Journal information: eLife Pavan Choppakatla et al, Linker histone H1.8 inhibits chromatin binding of condensins and DNA topoisomerase II to tune chromosome length and individualization,(2021). DOI: 10.7554/eLife.68918
