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How to unravel the DNA tangle
A computer simulation has unveiled the structure and function of the chromosome tangle, as a chromosome is rarely found in the shape we see in biology books, the typical double rod shaped X pattern.
DNA is usually “diluted” in the nucleus, creating a bundle that under the microscope appears as a messy tangle. In the last few years such chaos has been “measured” and scientists have unveiled a secretthe genes in the tangle are actually arranged in regions that may perform a functional role.
In research coordinated by the scientists at SISSA of Trieste, scientists have now developed a numeric model of the chromosome that supports their experimental dataand provides a hypothesis on the bundle’s function.
To the untrained eye, a chromosome within the nuclear
cytoplasm may look like a randomly entangled thread.
Yet, biologists claim the opposite.
Although chaotic components do exist within the bundle,
experimental measurements have identified regions
that tend to contain specific genes.
Thanks to extensive measurements, researchers have created maps of the human chromosome 19 in its diluted form, which shows where DNA transcription should occur.
Cristian Micheletti, a physicist at SISSA the International School for Advanced Studies at Trieste, has coordinated an international research team, led by Marco Di Stefano and Angelo Rosa stand, that has devised an ingenious method verifing the experimental data in support of a theory explaining how the DNA bundle is arranged in regions.
“Employing the vast amount of publicly available data
on gene expression, we have identified families
of genes co-regulated within a chromosome”
Cristian Micheletti, physicist
International School for Advanced Studies at Trieste
The co-regulated genes codify “in accord”, but how synchronization occurs is a mystery, as the genes are often located very far from one another on the DNA filament. Micheletti: “Two main hypotheses may be considered: either ‘messengers’ exist that travel back and forth from one gene to the other and coordinate the activity, or the DNA filament folding up inside the tangle brings the genes belonging to the same family physically close.”
Using the computer model, Micheletti and colleagues
have brought the DNA co-regulated genes of human
chromosome 19 closer together.
“The outcome of the simulation has provided a map
of chromosome arrangement that is very close
to the one obtained through experimentation.
The model has successfully brought genes belonging
to the same families closer together in 80% of cases,
with little difficulty, corroborating the validity of our
hypothesis and the effectiveness of the
computer model.”
Cristian Micheletti, physicist
The article was chosen by PLoS Computational Biology journal as the cover story for the March, 2013 issue.
Funding: We acknowledge financial support from the Italian Ministry of Education (MIUR), grant PRIN 2010HXAW77. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Original article: http://www.sissa.it/images/documents/form_e_documenti_linkati/
2013-03-29_Micheletti_cromosomi/Sbrogliare_il_groviglio_del_DNA_ENG.pdf
Author Summary
Recent high-throughput experiments have shown that chromosome regions (loci) which accommodate specific sets of coregulated genes can be in close spatial proximity despite their possibly large sequence separation. The findings pose the question of whether gene coregulation and gene colocalization are related in general. Here, we tackle this problem using a knowledge-based coarse-grained model of human chromosome 19. Specifically, we carry out steered molecular dynamics simulations to promote the colocalization of hundreds of gene pairs that are known to be significantly coregulated. We show that most () of such pairs can be simultaneously colocalized. This result is, in turn, shown to depend on at least two distinctive chromosomal features: the remarkably low degree of intra-chain entanglement found in chromosomes inside the nucleus and the large number of cliques present in the gene coregulatory network. The results are therefore largely consistent with the coregulation-colocalization hypothesis. Furthermore, the model chromosome conformations obtained by applying the coregulation constraints are found to display spatial macrodomains that have significant similarities with those inferred from HiC measurements of human chromosome 19. This finding suggests that suitable extensions of the present approach might be used to propose viable ensembles of eukaryotic chromosome conformations in vivo.
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