In order to fit DNA into the nucleus, it must be packaged into a highly compacted structure known as chromatin. In the first step of this process DNA is condensed into an 11 nm fiber that represents an approximate 6-fold level of compaction . This is achieved through nucleosome assembly.
The nucleosome is the smallest structural component of chromatin, and is produced through interactions between DNA and histone proteins. Here, a histone octamer is formed from the histones H2A, H2B, H3 and H4, although in some cases other histone variants may also be found in the core (e.g., H2A.Z, MacroH2A, H2a.Bbd, H2A.lap1, H2A.X, H3.3, CenH3 and others ). A 147bp segment of DNA then wraps around the histone octamer 1.75 times, thus completing the formation of a single nucleosome.
Of course, a single nucleosome will not form in isolation but is instead part of a wider process, whereby multiple nucleosomes form in a linear fashion along the DNA molecule. This ultimately produces the 11 nm fiber, which is traditionally described, based on its appearance, as “beads on a string” . Here, adjacent nucleosomes are connected via “linker DNA”, which is usually bound to the H1 histone and is between 20-80 bps long. Additionally, flexible histone tails which originate from the histone octamer extend away from nucleosomal DNA and can interact with other nucleosomes, stabilizing more complex 3D structures . In other words, specific nucleosomes can be far apart with respect to their linear sequence, but within interacting distance in the context of higher order chromatin structure .
Alternative nucleosome conformations (reviewed in ) may arise due to spontaneous unwrapping and rewrapping of DNA around the histone core, as well as due to variations in histones themselves. Moreover, nucleosomes are highly dynamic and can undergo spontaneous sliding, “splitting” or even complete dissociation.
The level of compaction attained through the formation of the 11 nm nucleosome fiber is insufficient to package the whole genome into the nucleus. Instead, this fiber forms the basis for other higher order chromatin structures that are established through additional folding and bending events.
Despite the extensive knowledge already gained on the structure of the 11 nm nucleosome fiber, as well as metaphase chromosomes, the intermediate chromatin structures commonly described are largely hypothetical and yet to be observed in vivo.
Two popular models that were proposed based on in vitro data are the solenoid and zigzag. In each case, the 11 nm nucleosome fiber undergoes additional folding to form a 30 nm fiber  with the manner of folding for a particular region depending on the internucleosomal linker length and the presence of linker histone H17 . In the one-start solenoid model, bent linker DNA sequentially connects each nucleosome cores, creating a structure where nucleosomes follow each other along the same helical path . Alternatively, in the two-start zigzag model, straight linker DNA connects two opposing nucleosome cores, creating the opposing rows of nucleosomes that form so called “two-start” helix. In zigzag model, alternate nucleosomes (for example, N1 and N3) become interacting partners . Interestingly, some studies offer a model, where intermediate 30 nm fibers contain both the solenoid and zigzag conformations , suggesting instead that observations made in in vitro experiments might be an isolation artifact due to strictly cationic low-salt environment or chemical cross-linking (e.g., glutaraldehyde fixation). Consequently, new models of 11 nm fiber compaction have been proposed (e.g., chromonema, chromatin hub, hybrid chromonema/chromatin hub, fractal ), but no common conclusion has been reached yet.
One aspect shared by most of the models for higher order chromatin organization is the dynamic existence of decondensed loops among more compact chromatin structures. In most cases, higher order chromatin has to be decondensed to a nucleosome structural level in order to transcribe genes . The length of the decondensed chromatin loop can sometimes exceed the area occupied by the chromosome territory, to which the loop belongs, allowing it to intermingle into the neighbouring chromosome territory .
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