Chromatin is a substance inside a chromosome made up of DNA and proteins. The main proteins in chromatin are histones, which help condition DNA in a compact form that fits into the cell nucleus. New research from the Weizmann Institute of Science has revealed a previously unknown mode of organization of nuclear chromatin in fully differentiated cells in which the chromatin density is high at the nuclear periphery and undetectable in the nuclear center, creating an effectively central region devoid of chromatin.
In a previous study, Dr Daria Amiad-Pavlov and colleagues at the Weizmann Institute of Science analyzed how mechanical forces influence cell nuclei in muscle and found evidence that muscle contractions had an immediate effect on patterns of gene expression.
“We couldn’t explore this further because the existing methods relied on imaging chemically conserved cells, so they failed to capture what is going on in the cell nuclei of an actual functioning muscle,” said Dr Amiad-Pavlov.
To solve this problem, the researchers sought to study the muscle nuclei of live fruit flies (Drosophila) larvae.
They obtained images of the linearly organized internal complexes of DNA and its proteins, surrounded by the membrane of muscle nuclei.
Rather than filling the entire volume of the nucleus, the “noodles,” or long molecules of chromatin, were organized into a relatively thin layer, attached to its inner walls.
Similar to the result of the interaction between oil and water, known as phase separation, chromatin separated from most of the liquid inside the nucleus and found its way to its periphery, while most of the fluid medium remained at the center.
Scientists realized they were about to tackle a fundamental biological question, namely how chromatin, and therefore DNA, is organized in the nucleus of a living organism.
“But the results were so unexpected that we had to make sure that no mistakes had crept in and that this organization was universal,” said Dr Dana Lorber, also of the Weizmann Institute of Science.
The authors also constructed a theoretical model including the physical factors governing the organization of chromatin in the nucleus, such as the relative forces of attraction between chromatin and its liquid environment and between chromatin and the nuclear membrane.
Their model predicts that chromatin should undergo liquid phase separation, depending on the relative amount of liquid (hydration) in the nucleus. In addition, the phase-separated chromatin could then arrange along the interior of the nuclear membrane – just as they had found in their experiments.
They also explained why chromatin seemed to fill cell nuclei in previous studies.
“When scientists plate cells on a glass slide in order to study them under a microscope, they change their volume and physically flatten them,” said Professor Samuel Safran of the Weizmann Institute of Science.
“This can disrupt some of the forces governing the arrangement of chromatin and reduce the distance between the top of the nucleus and its base.”
The team’s results were published in the journal Scientists progress.
Daria Amiad Pavlov et al. 2021. Live imaging of chromatin distribution reveals new principles of nuclear architecture and chromatin compartmentalization. Scientists progress 7 (23); doi: 10.1126 / sciadv.abf6251