Nuclear Structure and Function Research Group

The DNA molecules that run the length of each human chromosome are arguably the longest and most important biomolecules known. But although we now know the sequence of the millions of bases in the DNA of each of the 46 chromosomes, we still know little about how those bases are folded in 3-D space within the nucleus of a living cell. Common sense suggests that there must be some underlying order within the apparent tangle, and our current research is concerned with elucidating what that order might be, and how it affects gene function. Our ultimate goal is to generate structural and functional maps of nuclei using a multi-disciplinary approach (e.g., combining molecular analysis, high-resolution imaging, and computer modeling).

We are faced with a considerable problem. The human genome is made up of 23 pairs of DNA molecules that are incredibly thin and long, with a width of ~2 nm and a combined length of ~2 m. All 46 molecules must be packed into a nucleus only ~10 μm wide, a packing problem analogous to folding a kite string that stretches from New York to Chicago into a sphere 10 metres across. Real-sized DNA strings are probably packed into real-sized nuclei by a combination of coiling into higher-order spirals, looping by attachment to underlying structures, and random folding (like pasta in a bowl). Yet this tangle must still allow individual genes to perform their functions; for example, inheritance requires that each DNA molecule must be copied exactly and sorted precisely so that each daughter cell receives one copy.

We have suggested one model for the organization, and how that organization is related to function. We suggest that different copying machines – RNA polymerases – scattered along the chromosome cluster together into "factories" to loop the intervening DNA, and that the copying machines are transiently immobilized whilst they are active (see this essay). And just as car factories contain the relevant machines and raw materials concentrated in one place to facilitate car production, transcription factories contain the enzymes and other molecules that can quickly and efficiently copy DNA into RNA. Moreover, much as one car factory might make a Honda and another a Mercedes, we suggest that one transcription factory will selectively copy certain genes to the exclusion of others. We also imagine that tethering a gene close to the relevant factory containing the appropriate machinery will enhance efficient copying, so the system is regulated by increasing or decreasing the lengths of relevant tethers (illustrated in a 5-min YouTube movie).

In collaboration with engineers – and in a complete departure of what we have done previously – we are also developing simple ways of miniaturizing the workflows used in biomedicine. We hope these will transform the way small volumes are handled. iotaSciences Ltd – a company spun-out from The University of Oxford – is commercializing this technology.

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