Chromatin is the complex combination of DNA and proteins that makes up chromosomes. It is found inside the nuclei of eukaryotic cells. It is divided between heterochromatin (condensed) and euchromatin (extended) forms.  The major components of chromatin are DNA and histone proteins, although many other chromosomal proteins have prominent roles too. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. Chromatin contains genetic material-instructions to direct cell functions. Changes in chromatin structure are affected by chemical modifications of histone proteins such as methylation (DNA and proteins) and acetylation (proteins), and by non-histone, DNA-binding proteins.
In simple terms, there are seven levels of chromatin organization (Fig. 1):
During spermiogenesis, the spermatid's chromatin is remodelled into a more spaced-packaged, widened, almost crystal-like structure. This process is associated with the cessation of transcription and involves nuclear protein exchange. The histones are mostly displaced, and replaced by protamines (small, arginine-rich proteins).
It should also be noted that, during mitosis, while most of the chromatin is tightly compacted, there are small regions that are not as tightly compacted. These regions often correspond to promoter regions of genes that were active in that cell type prior to entry into cromitosis. The lack of compaction of these regions is called bookmarking, which is an epigenetic mechanism believed to be important for transmitting to daughter cells the "memory" of which genes were active prior to entry into mitosis. This bookmarking mechanism is needed to help transmit this memory because transcription ceases during mitosis.
The structure of chromatin during interphase is optimised to allow easy access of transcription and DNA repair factors to the DNA while compacting the DNA into the nucleus. The structure varies depending on the access required to the DNA. Genes that require regular access by RNA polymerase require the looser structure provided by euchromatin.
Chromatin undergoes various forms of change in its structure. Histone proteins, the foundation blocks of chromatin, are modified by various post-translational modification to alter DNA packing. Acetylation results in the loosening of chromatin and lends itself to replication and transcription. When certain residues are methylated they hold DNA together strongly and restrict access to various enzymes. A recent study showed that there is a bivalent structure present in the chromatin: methylated lysine residues at location 4 and 27 on histone 3. It is thought that this may be involved in development; there is more methylation of lysine 27 in embryonic cells than in differentiated cells, whereas lysine 4 methylation positively regulates transcription by recruiting nucleosome remodeling enzymes and histone acetylases.
The vast majority of DNA within the cell is the normal DNA structure. However in nature DNA can form three structures, A-, B- and Z-DNA. A and B chromosomes are very similar, forming right-handed helices, while Z-DNA is a more unusual 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.
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 the core histones, there is the linker histone, H1, which 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 10 nm "beads-on-a-string" fibre. (Fig. 1-2). .
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, adenosine and thymine are more favorably compressed into the inner minor grooves. This means nucleosomes can bind preferentially at one position approximately every 10 base pairs (the helical repeat of DNA)- where the DNA is rotated to maximise the number of A and T bases that will lie in the inner minor groove. (See mechanical properties of DNA.)
With addition of H1, the "beads-on-a-string" structure in turn coils into a 30 nm diameter helical structure known as the 30 nm fibre or filament. The precise structure of the chromatin fibre in the cell is not known in detail, and there is still some debate over this.
This level of chromatin structure is thought to be the form of euchromatin, which contains actively transcribed genes. EM studies have demonstrated that the 30 nm fibre 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 length of the linker DNA should produce different folding topologies of the chromatin fiber. Recent theoretical work, based on electron-microscopy images of reconstituted fibers support this view.
The layout of the genome within the nucleus is not random - specific regions of the genome have a tendency to be found in certain spaces. Specific regions of the chromatin are enriched at the nuclear membrane, while other regions are bound together by protein complexes. The layout of this is not, however, well characterised apart from the compaction of one of the two X chromosomes in mammalian females into the Barr body. This serves the role of permanently deactivating these genes, which prevents females getting a 'double dose' relative to males. The extent to which the inactive X is actually compacted is a matter of some controversy.
Fluctuations between open and closed chromatin may contribute discontinuity of transcription, or transcriptional bursting. Other factors are probably involved, such as the association and dissociation of transcription factor complexes with chromatin. The phenomenon, as opposed to simple probabilistic models of transcription, can account for the high variability in gene expression occurring between cells in isogenic populations.
The metaphase structure of chromatin differs vastly to that of interphase. It is optimised for physical strength and manageability, forming the classic chromosome structure seen in karyotypes. The structure of the condensed chromosome is thought to be loops of 30 nm fibre to a central scaffold of proteins. It is, however, not well characterised.
The physical strength of chromatin is vital for this stage of division to prevent shear damage to the DNA as the daughter chromosomes are separated. To maximise strength the composition of the chromatin changes as it approaches the centromere, primarily through alternative histone H1 anologues.
The proteins that are found associated with isolated chromatin fall into several functional categories:
Proteins associated with chromatin are those involved in DNA transcription, replication and repair, and in post-translational modification of histones. They include various types of nucleases and proteases. Scaffold proteins encompass chromatin proteins such as insulators, domain boundary factors and cellular memory modules (CMMs).
The following scientists were recognized for their contributions to chromatin research with Nobel Prizes:
|1910||Albrecht Kossel (University of Heidelberg)||Nobel Prize in Physiology or Medicine "in recognition of the contributions to our knowledge of cell chemistry made through his work on proteins, including the nucleic substances"|
|1933||Thomas Hunt Morgan (California Institute of Technology)||Nobel Prize in Physiology or Medicine "for his discoveries concerning the role played by the chromosome in heredity"|
|1962||Francis Crick, James Watson and Maurice Wilkins (MRC Laboratory of Molecular Biology, Harvard University and London University respectively)||Nobel Prize in Physiology or Medicine "for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material"|
|1982||Aaron Klug (MRC Laboratory of Molecular Biology)||Nobel Prize in Chemistry "for his development of crystallographic electron microscopy and his structural elucidation of biologically important nucleic acid-protein complexes"|
|1993||Roberts and Sharp||Nobel Prize in Physiology "for their independent discoveries of split genes"|
|2006||Roger Kornberg (Stanford University)||Nobel Prize in Chemistry "for his studies of the molecular basis of eukaryotic transcription"|
Chromatin is divided into heterochromatin (condensed) and euchromatin (extended) forms. The major components of chromatin are DNA and histone proteins, although other proteins also occur. The functions of chromatin are:
Chromatin contains genetic material: instructions to direct cell functions. Changes in chromatin structure are one way the action of genes is controlled.