Project description

Haemoglobin disorders, such as sickle cell disease and β-thalassaemia are the result of mutations in the adult β-globin gene. When these disorders are co-inherited with hereditary persistence of fetal haemoglobin, (high levels of γ-globin gene expression in adult life) the disease phenotype is much reduced. Understanding the mechanism of γ-globin globin gene regulation through development has been the subject of intense investigation for many years. These studies led to an appreciation of the role of epigenetic modifications such as DNA methylation and histone acetylation in globin gene expression and regulation. Networks of regulatory proteins interact with epigenetic complexes to regulate DNA accessibility and histone modifications, thereby determining appropriate patterns of globin gene expression, giving rise to several developmental stage-specific hemoglobin variants.

This study will investigate the potential impact of epigenetic regulators on globin gene expression. Functional genomic screening strategies will be performed using RNA interference (RNAi) or CRISPR/Cas9 genome editing to either suppress or knockout the expression of specific epigenetic regulators in erythroid cells modified to express fluorescent reporter genes under the control of the γ-globin promoter. Further studies will also be conducted in vivo using unique humanised β-thalassaemia mouse models. Positive outcomes of such studies could pave the way for better treatment strategies for sickle cell anaemia and β-thalassaemia patients by targeting epigenetic regulators to increase fetal globin expression.