Chromatin

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.
The primary protein components of chromatin are histones. An octamer of two sets of four histone cores bind to DNA and function as "anchors" around which the strands are wound. In general, there are three levels of chromatin organization:

DNA wraps around histone proteins, forming nucleosomes and the so-called beads on a string structure.
Multiple histones wrap into a 30-nanometer fiber consisting of nucleosome arrays in their most compact form.
Higher-level DNA supercoiling of the 30 nm fiber produces the metaphase chromosome.

Many organisms, however, do not follow this organization scheme. For example, spermatozoa and avian red blood cells have more tightly packed chromatin than most eukaryotic cells, and trypanosomatid protozoa do not condense their chromatin into visible chromosomes at all. Bacterial cells have entirely different structures for organizing their DNA. Many archaea, however, do encode histone proteins, and wrap DNA into nucleosome-like assemblies of different sizes, so called hypernucleosomes.
The overall structure of the chromatin network further depends on the stage of the cell cycle. During interphase, the chromatin is structurally loose to allow access to RNA and DNA polymerases that transcribe and replicate the DNA. The local structure of chromatin during interphase depends on the specific genes present in the DNA. Regions of DNA containing genes which are actively transcribed are less tightly compacted and closely associated with RNA polymerases in a structure known as euchromatin, while regions containing inactive genes are generally more condensed and associated with structural proteins in heterochromatin. Epigenetic modification of the structural proteins in chromatin via methylation and acetylation also alters local chromatin structure and therefore gene expression. There is limited understanding of chromatin structure and it is active area of research in molecular biology.

Dynamic chromatin structure and hierarchy

Chromatin undergoes various structural changes during a cell cycle. Histone proteins are the basic packers and arrangers of chromatin and can be modified by various post-translational modifications to alter chromatin packing. Most modifications occur on histone tails. The positively charged histone cores only partially counteract the negative charge of the DNA phosphate backbone resulting in a negative net charge of the overall structure. An imbalance of charge within the polymer causes electrostatic repulsion between neighboring chromatin regions that promote interactions with positively charged proteins, molecules, and cations. As these modifications occur, the electrostatic environment surrounding the chromatin will flux and the level of chromatin compaction will alter. The consequences in terms of chromatin accessibility and compaction depend both on the modified amino acid and the type of modification. For example, histone acetylation results in loosening and increased accessibility of chromatin for replication and transcription. Lysine trimethylation can either lead to increased transcriptional activity or transcriptional repression and chromatin compaction. Several studies suggested that different modifications could occur simultaneously. For example, it was proposed that a bivalent structure is involved in early mammalian development. Another study tested the role of acetylation of histone 4 on lysine 16 on chromatin structure and found that homogeneous acetylation inhibited 30 nm chromatin formation and blocked adenosine triphosphate remodeling. This singular modification changed the dynamics of the chromatin which shows that acetylation of H4 at K16 is vital for proper intra- and inter- functionality of chromatin structure.
Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.
For additional information, see Chromatin variant, Histone modifications in chromatin regulation and RNA polymerase control by chromatin structure.

Structure of DNA

In nature, DNA can form three structures, A-, B-, and Z-DNA. A- and B-DNA are very similar, forming right-handed helices, whereas Z-DNA is a left-handed helix with a zig-zag phosphate backbone. Z-DNA is thought to play a specific role in chromatin structure and transcription because of the properties of the junction between B- and Z-DNA.
At the junction of B- and Z-DNA, one pair of bases is flipped out from normal bonding. These play a dual role of a site of recognition by many proteins and as a sink for torsional stress from RNA polymerase or nucleosome binding. DNA bases are stored as a code structure with four chemical bases such as "Adenine, Guanine, Cytosine, and Thymine ". The order and sequences of these chemical structures of DNA are reflected as information available for the creation and control of human organisms. "A with T and C with G" pairing up to build the DNA base pair. Sugar and phosphate molecules are also paired with these bases, making DNA nucleotides arrange 2 long spiral strands unitedly called "double helix". In eukaryotes, DNA consists of a cell nucleus and the DNA is providing strength and direction to the mechanism of heredity. Moreover, between the nitrogenous bonds of the 2 DNA, homogenous bonds are forming.

Nucleosomes and beads-on-a-string

The basic repeat element of chromatin is the nucleosome, interconnected by sections of linker DNA, a far shorter arrangement than pure DNA in solution.
In addition to core histones, a linker histone H1 exists that contacts the exit/entry of the DNA strand on the nucleosome. The nucleosome core particle, together with histone H1, is known as a chromatosome. Nucleosomes, with about 20 to 60 base pairs of linker DNA, can form, under non-physiological conditions, an approximately 11 nm beads on a string fibre.
The nucleosomes bind DNA non-specifically, as required by their function in general DNA packaging. There are, however, large DNA sequence preferences that govern nucleosome positioning. This is due primarily to the varying physical properties of different DNA sequences: For instance, adenine, and thymine is more favorably compressed into the inner minor grooves. This means nucleosomes can bind preferentially at one position approximately every 10 base pairs - where the DNA is rotated to maximise the number of A and T bases that will lie in the inner minor groove.

30-nm chromatin fiber in mitosis

With addition of H1, during mitosis the beads-on-a-string structure can coil into a 30 nm-diameter helical structure known as the 30 nm fibre or filament. The precise structure of the chromatin fiber in the cell is not known in detail.
This level of chromatin structure is thought to be the form of heterochromatin, which contains mostly transcriptionally silent genes. Electron microscopy studies have demonstrated that the 30 nm fiber is highly dynamic such that it unfolds into a 10 nm fiber beads-on-a-string structure when transversed by an RNA polymerase engaged in transcription.
The existing models commonly accept that the nucleosomes lie perpendicular to the axis of the fibre, with linker histones arranged internally.
A stable 30 nm fibre relies on the regular positioning of nucleosomes along DNA. Linker DNA is relatively resistant to bending and rotation. This makes the length of linker DNA critical to the stability of the fibre, requiring nucleosomes to be separated by lengths that permit rotation and folding into the required orientation without excessive stress to the DNA.
In this view, different lengths of the linker DNA should produce different folding topologies of the chromatin fiber. Recent theoretical work, based on electron-microscopy images
of reconstituted fibers supports this view.

DNA loops

The beads-on-a-string chromatin structure has a tendency to form loops. These loops allow interactions between different regions of DNA by bringing them closer to each other, which increases the efficiency of gene interactions. This process is dynamic, with loops forming and disappearing. The loops are regulated by two main elements:

Cohesins, protein complexes that generate loops by extrusion of the DNA fiber through the ring-like structure of the complex itself.
CTCF, a transcription factor that limits the frontier of the DNA loop. To stop the growth of a loop, two CTCF molecules must be positioned in opposite directions to block the movement of the cohesin ring.

There are many other elements involved. For example, Jpx regulates the binding sites of CTCF molecules along the DNA fiber.

Spatial organization of chromatin in the cell nucleus

The spatial arrangement of the chromatin within the nucleus is not random - specific regions of the chromatin can be found in certain territories. Territories are, for example, the lamina-associated domains, and the topologically associating domains, which are bound together by protein complexes. Currently, polymer models such as the Strings & Binders Switch model and the Dynamic Loop model are used to describe the folding of chromatin within the nucleus. The arrangement of chromatin within the nucleus may also play a role in nuclear stress and restoring nuclear membrane deformation by mechanical stress. When chromatin is condensed, the nucleus becomes more rigid. When chromatin is decondensed, the nucleus becomes more elastic with less force exerted on the inner nuclear membrane. This observation sheds light on other possible cellular functions of chromatin organization outside of genomic regulation.