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Chromosomes as topological machines-the role of DNA thermodynamics

Wednesday 5th September 2012 - 10:10 to 10:50
INI Seminar Room 1
The chirality of the DNA molecule underpins its ability to partition superhelicity between twist and writhe. We argue that manipulation of superhelical density and of partitioning by topological devices and processive ATP-dependent motors (DNA and RNA polymerases and topoisomerases) is a fundamental property of both bacterial and eukaryotic chromosomes. On this view chromosomes act as machines in which topological transitions operate at several functional levels - local (e.g. transcription initiation sites), regional (constrained superhelical domains) and global (chromosomes) levels.

The partition between twist and writhe is dependent in part on the sequence of DNA. We have shown that in the E. coli chromosome gradients of DNA gyrase binding sites from the origin to the terminus of DNA replication along both replichores correlate with temporal patterns of gene expression during the growth cycle such that genes expressed during exponential growth are preferentially located in the Ori-proximal region. These observations imply that during exponential growth there exist gradients of superhelical density from the origin to the terminus. Intriguingly the chromosomal DNA sequences exhibit, on average, a gradient of DNA stacking energy in the same direction. We argue that this gradient in the physicochemical properties of DNA integrates the functional response to changes in superhelical density and to regulation by abundant nucleoid-associated proteins.

We further show that the genetic and chromatin organisation in yeast chromatin assembled both in vitro and in vivo is highly dependent on, the stacking/melting energies of DNA sequences. The regions of chromosomes that are sites for topological manipulation (such as transcription and replication initiation sites and preferred sites for topoisomerase II) correlate strongly with low stacking energies and high flexibility. Such regions concomitantly exhibit low nucleosome occupancy. We conclude that the most flexible DNA sequences are, counter-intuitively, poor substrates for octamer deposition. In contrast high nucleosome occupancy correlates with DNA sequences of moderately high stacking energies. In such relatively stiff sequences positioned nucleosomes can often be related to a bending anisotropy appropriate for nucleosome formation.
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University of Cambridge Research Councils UK
    Clay Mathematics Institute London Mathematical Society NM Rothschild and Sons