Haifa researchers use laser ‘tweezers’ to study structure and dynamics of DNA packaging in all cells
Each one of the cells in our bodies contains DNA, which dictates the instructions needed for living things to develop and function. Incredibly, a total of two meters of DNA is packaged in each tiny cell’s nucleus, which is just tens of microns in size. This is made possible to packaging the DNA into a compact structure called chromatin.
The basic level of chromatin organization is provided by wrapping the DNA around proteins called histones in a spool-like structure that resembles beads on a string. Then, more complex structures called chromatosomes are formed with the help of a special histone known as a linker histone that connects the strings.
But scientists have not known much about the structure and dynamics of chromatosomes, leaving the most basic questions of how they bind DNA.
Now, researchers in the Biology Faculty of the Technion-Israel Institute of Technology in Haifa have used “laser tweezers” to accomplish this. Their study, just published in the journal Molecular Cell under the title “Extended and dynamic linker histone-DNA Interactions control chromatosome compaction,” was conducted by Dr. Sergei Rudnizky under the supervision of Profs. Ariel Kaplan and hilippa Melamed.
Packaging of the genome is essential for it to fit into the cell, but it also reduces the accessibility to the cellular machines that read the DNA and transcribe the genes. Therefore, the distinct packaging at a particular gene will have a huge impact on its expression in ways that are only beginning to be unraveled.
In particular, linker histones are known to play a key role in this organization of the genome – and their malfunction can lead to serious diseases including cancer and autism.
The lack of understanding of these crucial processes stems from the dynamic nature of linker histones, which makes it challenging to investigate them using conventional methods based on sampling a huge number of molecules simultaneously.
Kaplan’s lab developed a unique method based on “optical tweezers” – an approach that allows researchers to capture individual chromatin molecules and exert forces on them with the help of a focused laser beam.
In these experiments, one strand of DNA is slowly detached from its complementary strand in a manner similar to a zipper being unzipped, through the entire structure of a chromatosome. The principle of the measurement is simple – at points where a histone makes contact with the DNA, even in the weakest way, the zipper gets stuck, and more force needs to be applied to overcome the histone-DNA contact and advance into the structure.
Using this approach, the team discovered that contacts between histones and DNA are far more extensive than previously known and that chromatosomes are, in fact, much larger than previously thought. They also they found a surprising flexibility in the structure of linker histones, as two different chromatosome shapes exist – one symmetric and compact and the second asymmetric and more relaxed.
Amazingly, transition between these shapes in an individual molecule can be externally controlled by the transcription machinery itself. This suggests that the cell uses the transition between stable and unstable forms of a chromatosome to regulate access to the DNA in a controlled manner. Given the key role played by chromatosomes in maintaining proper expression of our genome, these findings add an important layer to our understanding of the role of chromatin architecture in health and disease.
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