Everything about Chromatin totally explained
Chromatin is the complex of DNA and protein that makes up
chromosomes. It is found inside the
nuclei of
eukaryotic cells, and within the
nucleoid in prokaryotic cells.
The major
proteins involved in chromatin are
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. Changes in chromatin structure are affected mainly by
methylation (DNA and proteins) and
acetylation (proteins). Chromatin structure is also relevant to
DNA replication and
DNA repair.
Chromatin is easily visualised by staining, hence its name, which literally means
coloured material.
Basic Structure
Simplistically, there are three levels of chromatin organization (Fig. 1):
- DNA wrapping around nucleosomes - The "beads on a string" structure.
- A 30 nm condensed chromatin fiber consisting of nucleosome arrays in their most compact form.
- Higher level DNA packaging into the metaphase chromosome.
These structures don't occur in all eukaryotic cells. Examples of cells with more extreme packaging are
spermatozoa and
avian red blood cells.
During
spermiogenesis, the
spermatid's chromatin is remodelled into a more tightly packaged, compact, 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
mitosis. 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.
Levels of organization
The different levels of chromatin compaction are clearly visible in cells. In non-dividing cells there are two types of chromatin:
euchromatin and
heterochromatin. These correspond to uncompacted actively transcribed DNA and compacted untranscribed DNA. Recent evidence however, has revealed that these traditional fixed views of chromatin are not strictly correct and that both active and inactive genes can be found within chromatin regions of either type.
The structure of chromatin varies considerably as the
cell progresses through the
cell cycle. The changes in structure are required to allow the DNA to be used and managed, whilst minimising the risk of damage.
History
In 1882
Walther Flemming used the term
chromatin for the first time. Flemming assumed that within the nucleus there was some kind of
nuclear-scaffold. Furthermore, there were
nucleoli, the
nuclear plasm and the
nuclear membranes. He wrote (transl. from German): “The scaffold owes its capability of refraction, the way it behaves, and in particular its colorability to a substance which, with regard to its latter attribute, I've termed Chromatin. It is possible that this substance is really identical with the Nuclein-bodies. .... I’ll retain the name Chromatin as long as Chemistry has decided about it, and I empirically refer to it as that substance in the cell's nucleus which takes up the dye upon staining the nucleus ("Kerntinktionen").
During interphase
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.
Change in structure
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 methylated they hold DNA together strongly and restrict access to various enzymes. A recent study showed that there's 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's 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.
Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.
For additional information see
Histone modifications in chromatin regulation and
RNA polymerase control by chromatin structure
DNA structure
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 nucleosome and "beads-on-a-string"
» Main articles: Nucleosome, Chromatosome and Histone
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's the linker histone, H1, which contacts the exit/entry of the DNA strand on the nucleosome. The nucleosome, together with histone H1, is known as a chromatosome. Chromatosomes, connected by about 20 to 60 base pairs of linker DNA, form 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 is, however, some preference in the sequences the nucleosomes will bind. This is largely through the properties of DNA;
adenosine and
thymine are more favorably compressed into the inner minor grooves. This means nucleosomes bind preferentially at one position every 10 base pairs - where the DNA is rotated to maximise the number of A and T bases which will lie in the inner minor groove. (See
mechanical properties of DNA.)
30 nm chromatin fibre
The "beads-on-a-string" structure in turn coils into a 30 nm diameter helical structure known as the 30nm fibre or filament. The precise structure of the chromatin fibre in the cell isn't known in detail, and there's 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 the 30 nm fibre is highly dynamic such that it unfold 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.
Spatial organization of chromatin in the cell nucleus
The layout of the
genome within the nucleus isn't random - specific regions of the genome are always found in certain areas. Specific regions of the chromatin are thought to be bound to 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' of relative to
males.
Metaphase chromatin
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 30nm 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.
Non-histone chromosomal proteins
The proteins that are found associated with isolated chromatin fall into several functional categories:
chromatin-bound enzymes
high mobility group (HMG) proteins
transcription factors
scaffold proteins
transition proteins (testis specific proteins)
protamines (present in mature sperm)
Enzymes 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).
Chromatin: alternative definitions
Simple and concise definition: Chromatin is DNA plus the proteins (and RNA) that package DNA within the cell nucleus.
A biochemists’ operational definition: Chromatin is the DNA/protein/RNA complex extracted from eukaryotic lysed interphase nuclei. Just which of the multitudinous substances present in a nucleus will constitute a part of the extracted material will depend in part on the technique each researcher uses. Furthermore, the composition and properties of chromatin vary from one cell type to the another, during development of a specific cell type, and at different stages in the cell cycle.
The DNA – plus – histone – equals – chromatin definition: The DNA double helix in the cell nucleus is packaged by special proteins termed histones. The formed protein/DNA complex is called chromatin. The structural entity of chromatin is the nucleosome.
Nobel Prizes
The following scientists were recognized for their contributions to chromatin research with Nobel Prizes:
Further Information
Get more info on 'Chromatin'.
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