Research Groups > Genome Function

Mammalian genomes contain tens of thousands of genes that are partitioned in a small number of chromosomes. Gene neighbourhoods and epigenetic differences at the chromatin level play major roles in defining whether genes are ‘on’ or ‘off’. Chromosome conformation varies between cell types and this inevitably places whole groups of genes in particular nuclear environments, such as regions in the nuclear interior that are rich in splicing factors; or next to transcription factories, where many RNA polymerases simultaneously transcribe different transcription units. Genome architecture within the interphase nucleus is inextricably linked with gene regulation.

Figure 1. Features of genome organisation in mammalian nuclei
Click on image to enlarge

Our main aim is to understand the molecular and structural processes that regulate gene expression in the context of the interphase nucleus. We are investigating the relationship between genome architecture and gene expression in embryonic stem (ES) cells, and differentiated systems. We have developed high-resolution imaging methods for the visualisation of spatial relationships within the nucleus (e.g. cryo-FISH), and aim to understand the contribution of nuclear positioning on gene expression. Using chromatin immunoprecipitation (ChIP), we have shown that poised RNA polymerase II complexes are bound in ES cells at inactive, ‘bivalent’ genes that are important for early ES cell differentiation. We are currently studying their activity and regulation. We have identified poised transcription factories and are investigating their association with inducible genes. We are using biochemical strategies to purify and determine the molecular make-up of transcription factories, towards devising genetic assays to directly test their roles in genome architecture and gene regulation.

Figure 2. Developmental regulator genes are bound by RNA polymerase II and enriched for monoubiquitinated histone H2A.
Click on image to enlarge

Figure 3. Association of active genes (red) with transcription factories (green) in T cells.