Associate Professor of Chromosome Biology
Our studies are directed at understanding the relevance of nuclear organisation to gene expression during erythropoiesis. Our ultimate aim is to gain better insight into transcriptional regulation and to contribute to an understanding of how normal transcription may be restored in disease. Erythroid cells differentiate over the course of a few days from committed blast-forming cells, through the pronormoblast stage where they are highly proliferative and begin to produce large quantities of haemoglobin, to a condensed pyknotic state when nuclei are finally extruded from the cells. During this process, erythroid-specific genes are switched on and transcribe heavily before being shut down, which makes this process an ideal model for following gene regulation.
The nucleus is a highly ordered but plastic body of chromatin and nuclear substructures. Chromatin organisation within the nucleus has a key role to play in the processes of transcription and replication but the mechanisms governing how chromatin domains are established and altered during the course of development and differentiation remain poorly understood. Many genes, particularly those expressed in a tissue-specific manner, are regulated by enhancer elements that can lie at some distance from the target gene. There is a broad consensus that enhancer elements exert their effect on gene promoters by close interaction but many questions remain about what may drive such formations, how long they are stable for and how close is close ie are molecular interactions required or is a diffusible compartment established, enriched in factors required for upregulated transcription?
We are focusing on the organisation of chromatin around the α-globin genes, looking at what changes in decondensation and interactions are necessary for transcription, by imaging the positioning of DNA and RNA probes within single cells, both normal and from a panel of knockouts at regulatory sites across the region. Such analysis is an essential complement to the whole cell population studies of chromatin configurations undertaken within the Unit. To understand the dynamics of spatial organisation at the α-globin gene regulatory region during commitment, differentiation and transcription, we are developing systems in which we can visualise looping and transcription in real time in live cells.
In addition to these fundamental aspects of gene regulation we continue to characterise disorders of red blood cells. Having identified a second gene underlying congenital dyserythropoietic anaemia type 1 (CDA-I) we are undertaking functional studies to investigate the role that the two CDA-I genes, CDAN1 and c15orf41, play in normal erythropoiesis, and why mutations in either of these genes cause such devastating disruption to chromatin structure in differentiating erythroblasts.
An integrated platform to systematically identify causal variants and genes for polygenic human traits
Downes D. et al, (2019)
Stabilization of chromatin topology safeguards genome integrity
Ochs F. et al, (2019), Nature, 574, 571 - 574
Majeed syndrome: description of a novel mutation and therapeutic response to bisphosphonates and IL-1 blockade with anakinra.
Roy NBA. et al, (2019), Rheumatology (Oxford)
Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains.
Oudelaar AM. et al, (2018), Nat Genet, 50, 1744 - 1751
A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.
Brown JM. et al, (2018), Nat Commun, 9