Nuclear organisation and erythropoiesis

Every time a cell switches on its alpha globin genes to make haemoglobin, the DNA inside its nucleus must physically rearrange itself—and this project will watch that process happen in real time, one cell at a time. The problem is that we know the genetic code for alpha globin, but not how the cell’s machinery actually accesses that code. DNA is tightly coiled around proteins into chromatin, and for a gene to be active, that chromatin must loosen and change shape. Current maps show where regulatory sequences and epigenetic marks sit on chromosome 16, but they are static snapshots from millions of cells averaged together. This project will track the three-dimensional organisation of chromatin around the alpha globin genes in individual living cells, both when the genes are active and when they are silent. It will also ask whether DNA replication in that region alters gene activity. This is fundamental science with no immediate practical application. Understanding how chromatin conformation controls gene switching is a basic biological question. However, similar fundamental work on gene regulation has already enabled technologies like CRISPR and synthetic biology. A clearer picture of how cells physically turn genes on and off could, in the long term, inform new strategies to reactivate silenced globin genes in patients with inherited anaemias such as sickle cell disease or thalassaemia.