mapping chromatin and understanding epigenetics

A very interesting problem is that of why do cells differ in their formation and in structures. Bone cells in bone being different to say liver cells in liver.
Yet they have identical genome structure. Even more complicated are multicellular structures.
The basis of this different form lies in the chromatin state. Chromatin is the combination of histones and other proteins in a package with the DNA. In an explanatory article Baylin and Schuebel ( The epigenomic era opens 2007 Nature 448, 548-9 )describe chromatin as the software for the readout of the DNA hard drive.
If there is a change in the hard drive ie in the primary sequence of the DNA then a genetic alteration or mutation occurs
If the change is due to a change in the chromatin then there is an epigenetic change which is an alteration in the heritable states of DNA function. This is the expression and interaction of genes especially during the development process. There is no change in gene structure. Epigenetic change is the mechanism whereby there is flexibility in gene expression and the same genome package produces different cellular structures in the same organism.,
The central unit of chromatin is the nucleosome, which is constructed from short regions of DNA wound around an octet of histone proteins. This unit can modulate the readout from DNA in at least three ways.
1. nucleosomes can be physically rearranged on DNA by complexes known as chromatin-remodelling proteins, the greater the distance between nucleosomes, and hence the ‘openness’ of chromatin, the higher the likelihood that such regions of DNA will be transcribed into RNA.
2. many nucleosomes can be compacted into higher-order aggregates to form closed chromatin, or heterochromatin, thereby preventing transcription. The balance between the open and closed parts of the genome facilitates proper gene-expression patterns in given cell types, and also prevents unwanted gene transcription.
3. there is a complex interplay between enzymes that can modify particular amino acids in the histone component of the nucleosomes, and those that reverse the modifications. The modifications, or histone ‘marks’ interact with proteins that bind to and interpret them. The marks were initially seen as a histone code’, the idea being that a restricted number of them would specify the ‘on’ or off state of RNA production from DNA .
4. the constituents of chromatin, and nucleosome structure, position .and modification, are highly complex. It is a balance between these factors that marks an individual gene, or groups of genes, for various levels and states of expression”.
. Mikkelsen T S, et al in a paper entitled
Genome-wide maps of chromatin state in pluripotent and lineage-committed cells 2007 Nature 448 553-9 report the application of single-molecule-based sequencing technology for profiling histone modifications in mammalian cells. They found that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation.
Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions.This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.

Martin Eastwood
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