The impact of genome organization on its maintenance of integrity.
Genome organization and function
The mammalian genome is organized within the nucleus to cluster together certain regions at a shared sub-compartment to accommodate a specific function. The most recognisable example of this is the nucleolus, the site of ribosomal RNA production, which brings together multiple genes that are positioned on several chromosomes. Yet many other nuclear functions are also clustered into sub-compartments, thus bringing together different regions of the genome.
The organizing influence of transcription
Transcription is one of the most fundamental activities to occur within the nucleus and is also compartmentalised, taking place at small (~100 nm diameter), discrete centres called transcription factories. Our evidence suggests that each transcription factory can accommodate more than one gene at the same time, and thus can be viewed as hubs where actively transcribed genes congregate. Of significance, genes do not merely migrate randomly to any transcription factory, but instead exhibit a preference to be at a factory with certain other groups of genes. Not surprisingly, genes in cis are often transcribed together, perhaps due to their natural proximity to each other. However, a high occurrence of co-association can be detect between genes on separate chromosomes. The driving force that underlies these preferred co-associations is not well understood, yet may relate to shared pathways of regulation.
The dangers of proximity
Concurrent occupation of a transcription factory implies that genes come into close contact with each other, in a transcription-dependent manner. We have postulated that it is at these moments when genes may be particularly susceptible to DNA damage, such as breaks in the strands, that may be followed by errors in repair leading to a chromosomal translocation. Indeed, we have observed that the recurrent chromosomal translocation partner genes, Myc and Igh, which account for the majority of Burkitt’s lymphoma in humans, co-associate at the same transcription factory at remarkably high frequencies. We predict that this transcription-mediated juxtaposition, coupled with coincidental DNA breakage, and followed by aberrant repair, can lead to the formation of a chromosomal translocation.
The big questions
Using a combination of high-through-put, genome-wide analyses and fluorescence- microscopy methods, our research is directed at understanding some key principles.
- How does the frequency of chromosomal translocation events correspond to the frequency at which genes are typically transcribed at the same transcription factory?
- What are the driving forces that determine how often genes are likely to transcribe at the same factory?
- What mechanisms are in place to counteract DNA damage that occurs at transcription factories?
- How do chromosomal translocations alter both cis and trans interactions, and genomic organization in general?
Updated 22 August, 2011