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Watching DNA interact inside a cell
The total length of DNA inside a cell nucleus is somewhere between 2 and 3 meters. That is a tremendous length and a whole lot of information to be fit into the nucleus of an averaged size 0.1mm cell. In order to make it fit, the DNA is wrapped around small protein spindles called histones, just like thread is wrapped around a spool. It takes eight histone spools to wrap a little less than two turns of DNA. From then on, those eight wrapped histone spools are referred to as a histone octamer. Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4 (H standing for heterochromatin protein).
Altogether, this string of histones is called a nucleosome. It is coiled with chromatin protein to form a chromatin complex, and compactly sits inside the cell nucleus. However, being tightly compacted it is hard for cell machinery to access and interpret the DNA.
Structural studies of chromatin, so far, have only been static images of how DNA is organized within the cell. But, the question loomed: 'how can gene-expression machinery access DNA buried so deeply in chromatin?' The answer required a dynamic view of how genetic material interacts.
Now, the lab of Beat Fierz at École polytechnique fédérale de Lausanne (EPFL) in collaboration with Claus Seidel at the University of Düsseldorf, together observed actual chromatin in motion. Using a unique combination of protein and DNA chemistry, along with two complementary single-molecule fluorescence spectroscopy approaches, for the first time, their work reveals how the internal structure and movement of chromatin allows access to DNA.
Their research appears in Nature Communications, revealing that nucleosomes tangled within chromatin fibers form short stacks that quickly fall apart and reform within a matter of milliseconds. These short nucleosome packages contain four nucleosomes and about 800 base pairs of DNA — forming the basic unit of chromatin organization.
A protein that is responsible for gene silencing (heterochromatin protein 1a), can lock nucleosome interactions and compact chromatin even more — thus preventing gene expression machinery from accessing DNA.
Together, this discovery of such rapid dynamic transitions within chromatin provides new insight into how cell processes can either gain access or be phohibited access to DNA.
The dynamic architecture of chromatin fibers, a key determinant of genome regulation, is poorly understood. Here, we employ multimodal single-molecule Förster resonance energy transfer studies to reveal structural states and their interconversion kinetics in chromatin fibers. We show that nucleosomes engage in short-lived (micro- to milliseconds) stacking interactions with one of their neighbors. This results in discrete tetranucleosome units with distinct interaction registers that interconvert within hundreds of milliseconds. Additionally, we find that dynamic chromatin architecture is modulated by the multivalent architectural protein heterochromatin protein 1? (HP1?), which engages methylated histone tails and thereby transiently stabilizes stacked nucleosomes. This compacted state nevertheless remains dynamic, exhibiting fluctuations on the timescale of HP1? residence times. Overall, this study reveals that exposure of internal DNA sites and nucleosome surfaces in chromatin fibers is governed by an intrinsic dynamic hierarchy from micro- to milliseconds, allowing the gene regulation machinery to access compact chromatin.
Authors: Sinan Kilic, Suren Felekyan, Olga Doroshenko, Iuliia Boichenko, Mykola Dimura, Hayk Vardanyan, Louise C. Bryan, Gaurav Arya, Claus A. M. Seidel & Beat Fierz
Sandoz Family Foundation
Swiss National Science Foundation
European Research Council (Consolidator Grant 2017, chromo-SUMMIT)
Boehringer Ingelheim Foundation
European Research Council (Advanced Grant 2015, hybridFRET)
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Illustration of chromatin (on the left) opening up to individual nucleosomes (right). Tangled with chromatin fibers, nucleosomes form short stacks that quickly fall apart, but reform within a matter of milliseconds allowing cell machinery interaction with DNA.
Image credit: Beat Fierz/EPFL