#Infodump5
#Infodump5
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In case of human diploid cells, 2 meters of DNA is required to fit into nucleus of 10-15μm diameter. For a bigger impact of the previous statement, human cell has enough DNA to be wrapped around the cell more than 15,000 times.
DNA packaging allows this excessive DNA to fit nicely in a cell that is several times smaller.
Terminologies:
Terminologies:
Within the cell DNA is associated to proteins. Each DNA and its associated proteins are referred to as chromosome.
Proteins binding to DNA are divided into two classes: histones and non-histones. Majority of the associated proteins are positively charged (basic) proteins called histones. These proteins have an essential function of DNA compaction.
A given region of DNA with associated proteins (including histones and non-histones) is called as chromatin.
Bacteria don't have histones. However, they do have other basic proteins serving the same function i.e. DNA compaction.
Importance of DNA packaging:
Importance of DNA packaging:
Allows folding of an organism's DNA into a compact structure that can readily fit inside a cell.
Protects DNA from damage: Naked DNA is unstable, on contrary, chromosomal DNA is extremely stable.
DNA packaged into chromosome can be easily transmitted to both daughter cells each time the the cell divides.
The packaging allows DNA organization which facilitates gene expression and recombination.
Levels of DNA compaction:
Levels of DNA compaction:
Nucleosomes (11 nm)
Nucleosomes (11 nm)
Histones are responsible for the first level of compaction/ chromosome organisation, the Nucleosome. Hence, nucleosomes are also referred to as the building blocks of chromosomes.
Nucleosome constitutes 8 histone proteins (core histones) with DNA wrapped around them. This allows 6-fold compaction, the first step of final 1,000-10,000-fold eukaryotic DNA compaction.
Core DNA: ~147 bp DNA that is most tightly associated with nucleosome. This DNA wounds ~1.65 times around histone octamer (disc shaped histone core).
Linker DNA (bound to linker histone) : 20-60 bp DNA between each nucleosome.
Bond between DNA and histone: Hydrogen bond.
Histones are positively charged. This charge is attributable to the high content of positively charged amino-acids that making up the protein. These proteins have >20% of lysine and arginine.
Types of histone:
Core histone (11-15 kd): H2A, H2B, H3 and H4
Linker histone (20 kd): H1
H1 aids in strengthening the DNA-nucleosome association.
Nucleosome Assembly: H2A and H2B form a dimer, H2A-H2B. Similarly, H3 and H4 form a dimer, H3-H4, which then tetramerizes with other H3-H4. This H3-H4 tetramer binds to DNA causing two H2A-H2B dimers to join the complex and ultimately form nucleosome.
Histone Construction
Histone Construction
As depicted, the tails in the core histone are the N-terminal extensions that lack a definite structure. Since the tails are free (not a part of the core), they form an accessible site for modifications including methylation, acetylation and phosphorylation. Such modifications play a major role in gene expression and possibly in formation of higher order nucleosome structures. Furthermore, these tails enable stabilisation of DNA wrapping the histone core.
Nucleosome Remodelling
Nucleosome Remodelling
Nucleosome remodelling (depicted below) requires ATP as the energy source.
This flexible/dynamic nature aids in responding to developmental, metabolic and environmental cues by altering the accessibility of DNA regions.
30 nm and beyond
30 nm and beyond
H1, interestingly, stabilises this higher level of DNA compaction.
The N-terminal tails of the core histone too play a role in stabilisation of the 30 nm compaction by interacting with adjacent nucleosomes.
30 nm compaction constitutes 2 models: solenoid model (linker DNA does not pass through the central axis) and zig-zag model (linker DNA passes through the central axis hence, longer linker DNA prefers this conformation).
~40 fold compaction is achieved.
Further compaction requires nuclear scaffold to form (hold) the nuclear loops (as seen in DNA compaction diagram: 300 nm compaction).
Histone variants leads to interaction modifications:
Histone variants leads to interaction modifications:
H2A.z, a variant of H2, inhibits the formation of compact chromatin structures. This allows more regions of the DNA to be 'exposed' i.e. easily accessible. The DNA is more compatible for transcriptions.
CENP-A, a histone variant that replaces H3, has a longer N-terminal tail than H3. This replacement leads to alterations in nucleosomes at centromere/kinetochore as well as modify protein interactions.
DID YOU KNOW??
DID YOU KNOW??
The 1930s light microscope studies revealed that in eukaryotic cells the chromatin is of two types namely, heterochromatin and euchromatin. The 30 nm fibres and DNA loops discussed so far represent the euchromatin.
Coming up next: Nucleosome Assembly
References:
James D. Watson, Tania A. Baker, Stephen P. Bell, Alexander Gann, Michael Levine, Richard Losick - Molecular Biology of the Gene (2013, Benjamin Cummings) .
Fahy, G. M. (2019). First hint that body’s ‘biological age’ can be reversed. Aging Cell. https://doi.org/10.1111/acel.13028.
Lee, J., Kim, E.W., Croteau, D.L. et al. Heterochromatin: an epigenetic point of view in aging. Exp Mol Med (2020). https://doi.org/10.1038/s12276-020-00497-4.
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