β-haemoglobinopathies such as sickle-cell anaemia and β-thalassemia are among the world’s most common monogenic diseases. These diseases result from mutations in the β-globin gene that code for adult haemoglobin, resulting in improper functioning and impaired oxygen transport. Current treatments are short-term, have several adverse side effects and require lifelong administration. With the increasing socioeconomic burden associated with the disease, an effective long-term treatment is needed to overcome these limitations.
Reactivation of the developmentally silenced foetal γ-globin haemoglobin gene can alleviate symptoms of β-haemoglobinopathies by compensating for the dysfunctional adult haemoglobin. Key transcriptional regulators have been identified in recent years that control the developmental switch between foetal and adult haemoglobin. The aim of our research is to explore a transcriptional repressor called Zinc Finger and BTB Domain Containing 7A (ZBTB7A) that has been discovered to repress the foetal γ-globin gene. While the mechanism of repression is still unknown, we hypothesise that ZBTB7A’s ability to homodimerize via its BTB/POZ domain plays a key role in its binding to the foetal γ-globin gene to mediate γ-globin repression in adulthood.
We hypothesise that the silencing of the foetal haemoglobin gene is mediated by two ZBTB7A proteins interacting with each other via their BTB/POZ domains. By introducing an amino acid substitution at this interaction site in an erythroid cell model using CRISPR-Cas9 genome editing, we aim to abrogate ZBTB7A homodimerisation, thus disrupting ZBTB7A binding to turn back on the silenced foetal γ-globin gene. This strategy ultimately aims to elicit the mechanism and role of ZBTB7A to transcriptionally repress the foetal haemoglobin gene and could provide a therapeutic strategy for those affected with β-haemoglobinopathies.