Nuclear Structure and Function Research Group

Genome organization and gene regulation
    Human chromosomes are arguably the largest and most important biomolecules, but many aspects of their structure – and how structure affects function – remain unresolved. Our ultimate goal is to elucidate how the genome is folded, and how folding determines function. To this end, we apply a multi-disciplinary approach, combining molecular analyses, high-resolution imaging, and mathematical modeling.
    Our current focus is on the validation of our model for all genomes (see a 5-min YouTube movie), which is based on two heterodox concepts: (i) active polymerases are locally concentrated in discrete sites called ‘transcription factories’, and (ii) these molecular machines are immobilized when active. In other words, instead of tracking like locomotives down their templates, polymerases attached to factories reel in their templates as they extrude their transcripts. Then, these factories are both the active sites of transcription, and major organizers of the chromatin fibre (as active polymerases and associated transcription factors tether templates to the factories).
    We imagine that a promoter out in a loop initiates by binding to a factory containing the appropriate machinery, and that the frequency of initiation is determined by how closely that promoter is tethered to an appropriate factory. Then, regulatory motifs like enhancers (and silencers) act by tethering their target promoters close to (or distant from) suitable factories rich in the appropriate polymerases and factors.