Characterisation of the interplay of the COUP- TFII and BCL11A transcription factors in ?-globin regulation in fetal liver erythropoiesis

Context: From the moment of conception to the time of our first breath, the human body undergoes numerous transformative processes. One of these pivotal shifts is the transition from fetal to adult haemoglobin in our bloodstream. This seemingly straightforward process, known as the 'globin switch,' is instrumental in developing strategies to combat one of the world's most challenging and prevalent blood disorders: sickle cell disease (SCD). The challenge the project addresses: SCD, a disorder with a global footprint, arises when blood cells deform into a distinct 'sickle' shape because of a haemoglobin abnormality due to a single amino acid change in the ß-globin change. These misshapen cells often cluster together, causing blockages in small blood vessels, with subsequent hypoxia resulting in chronic pain syndromes, tissue necrosis, severe bacterial infections and other complications. The persistence of fetal haemoglobin after birth is known to counteract the negative effects of sickle haemoglobin. Thus, the prospect of rekindling the production of this type of haemoglobin in adulthood could revolutionise treatment. Aims and Objectives: Central to the objective of reactivating fetal haemoglobin are two molecular protagonists: BCL11A and COUP-TFII. While the former acts as a suppressor of fetal haemoglobin, the latter appears to promote its production. With these molecules as our guideposts, we have charted the following objectives: Deep Dive into Development: We aim to meticulously study the patterns and influences of BCL11A and COUP-TFII during a critical developmental phase of erythropoiesis within the fetal liver. This phase in haematopoiesis provides a perfect window to understand the nuances of fetal haemoglobin production and switching. Isolation and Growth: employing state-of-the-art techniques, our goal is to single out cells influenced by COUP-TFII and cultivate them. This will allow us to characterise them in greater detail. Molecular Exploration: By understanding the intricacies of these cells, we hope to uncover previously unknown details about the regulation of fetal haemoglobin production. Manipulative Studies: By altering the levels of BCL11A and COUP-TFII, we aim to define their impact and potential interplay on fetal haemoglobin production and switching. This would provide insights into potential therapeutic strategies. Potential Applications and Benefits: Approximately 5% of the world’s population are thought to carry genetic traits for haemoglobinopathies, namely sickle cell disease or thalassemia, equating to 300,000 babies with severe forms being born per year. At present, therapeutic measures, such as blood transfusion, hydroxyurea treatment and haematopoietic stem cell transplantation, may improve quality of life for patients with SCD. However, strategies aimed at maintaining, or increasing, the production of fetal haemoglobin well into adulthood by manipulating the interplay of BCL11A and COUP-TFII as regulators of the haemoglobin switch, may offer novel therapeutic opportunities. This approach has far-reaching implications, whereby understanding the mechanisms behind the globin switch could allow a shift to proactive intervention, preventing the onset of SCD entirely and providing insight into other genetic disorders. Furthermore, it could guide future research into genetic interventions, offering a blueprint for addressing other genetic disorders.