Our research focus is the organisation of chromatin within the nucleus and how that impacts on the gene regulation necessary for differentiation of cells from progenitor to specific cell types.
Alpha globin gene regulation
The three-dimensional organisation of the genome has only recently been understood to have a profound influence on gene regulation. Each genome is organised into sections or topologically associated domains (TADs) that encompass interactions between genes and their regulatory elements. Normally there is very little interaction between genes and elements in different TADs, so any disturbance of the TAD structure can lead to mis-regulation of gene expression and thence to human disease. Our research is focused on the spatial organisation of chromatin around the alpha globin locus as the genes become transcriptionally active during terminal erythroid differentiation. This is providing insight into fundamental mechanisms required for controlling gene expression. A looped domain of multiple chromatin interactions, with a three-dimensional structure, forms around the alpha globin genes during erythroid differentiation. We are investigating the timing, elements and processes necessary for this formation. We are also looking more broadly across the region to visualise the spatial relationship between neighbouring TADs as there is evidence that longer-range interactions do take place between active loci. We will feed this data into polymer models of the region to help us understand the rules governing the three-dimensional organisation of chromatin.
Congenital Dyserythropoietic Anaemia Type I
Ultra-fine bridges of DNA still connecting sets of chromosomes during cell division
One inherited erythroid disorder where chromatin organisation is disrupted is termed Congenital Dyserythropoietic Anaemia Type-I (CDA-I). The diagnostic feature of CDA-I is an abnormal appearance to heterochromatin within the nucleus when visualised by transmission electron microscopy. We have identified a new gene, C15ORF41, with mutations underlying this disease. The function of C15ORF41 is completely unknown. One other gene known to harbour mutations in CDA-I is CDAN1 encoding the protein Codanin-1. Codanin-1 is thought to be involved in regulating histone supply to the nucleus although it has no recognisable domains. Both proteins are widely expressed at low levels so it is unclear why this disease only affects the erythroid lineage. Characterisation of these two affected proteins promises to elucidate novel aspects in the regulation of erythropoiesis.