Thursday, 22 March 2012

Chromatin Structure and the Link to Cancer
Shane Fitzroy (42874171)


The DNA within malignant cancer cells can undergo further damage, even from chemo- or radio- therapy intended to treat cancer, resulting in errors such as deletions and duplications. These trigger further mutations within an already unregulated cell and possibly elevate it to an increased level of aggressive malignancy (Mirny 2011). These errors or somatic copy-number alterations (SCNAs) within cancerous cell genomes have long been observed to occur at specific locations within DNA and with varying frequencies depending on the type of cancer (Mirny 2011).

A hypothesis emerged, proposing that the three-dimensional spatial organisation of chromatin has a major influence on the occurrence of SCNA combinations within various cancer types previously documented. Previous limitations in visualising the architecture of chromatin in three-dimensions made exploring the hypothesis a challenge until a novel mapping technique known as Hi-C, a method that maps the physical structure of genomes at high-resolution, was used to accurately model the three-dimensional architecture of cancer cell genomes (Mirny 2011) (Dekker 2009).

A multidisciplinary team of scientists from MIT, the University of Massachusetts Medical School led by Harvard University, investigated the role that the newly discovered 3D “architecture” and organisation of chromatin had on the presence of DNA weak spots - locations within the chromatin mass that if traversed by repair enzymes simultaneously can result in translocations (Mirny 2011). These lead to large portions (loops) of DNA being excluded from the genome (Mirny 2011).
Statistical and visual modelling techniques showed that DNA's natural repair mechanism is actually a key contributor to further DNA mutation when repairing at certain locations within the fractal globule - a knotless, highly organised dense packing of chromatin (Mirny 2011 & Science News 2009).
Fig. 1 - New chromatin mass structure. Hi-C derived "Fractal Globule". (Dekker 2009)
Fig. 2 - DNA damage via loop (Mirny 2011)


So in other words, this chromatin layout is influencing the effectiveness and failure of DNA repair in locations with certain conformations. For example, repairing two or more existing errors simultaneously in DNA could cause major corruption if the sites of these errors are in close spatial proximity within the chromatin mass. Polymerases can join forming the closed loops that are cut from the genome by subsequent DNA repair efforts (Mirny 2011).
Fig. 3 - Contextual view (Mirny 2011)

 As you could imagine, losing this much genetic material could have a disastrous effect on the functioning of the entire cell, if future research indicates that consistently affected sections of DNA represent genes or other entities that play pivotal roles in regulating cell division or death in the case of cancerous cells.
This correlation between the 3D structure of chromatin and the instances of SCNAs respective to the type of cancer will play an important role in determining what sections of DNA will most likely be affected and, with extensive comparisons between many samples of cancerous cells, certain genes or other undetermined sequences of the human genome could be associated with a cumulative beneficial or negative effect on malignancy. In other words, this correlation will identify mutations that affect cell function.


References

Mirny, M. L. et. al. 2011, 'High order chromatin architecture shapes the landscape of chromosomal alterations in cancer', Nature Biotechnology, vol. 29, no. 12, pp. 1109-1113.
(Primary reference: http://www.nature.com/nbt/journal/v29/n12/full/nbt.2049.html)

Dekker, J. et. al. 2009, 'Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome', Science, vol. 326, no. 5950, pp. 289-293.

Dekker, J. & Lander, S. 2009, Hi-C: A Method to Study the Three-dimensional Architecture of Genomes, 5 June, Journal of Visualized Experiments, viewed 17 March 2012, .

Science News 2009, 3-D Structure of Human Genome: Fractal Globule Architecture Packs Two Meters of DNA Into Each Cell, viewed 19 March 2012, .

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