The β-globin locus is an archetypal model of developmental gene regulation, with a complex series of regulatory interactions controlling the stage-specific expression of different globin proteins, a process termed globin switching. An improved understanding of this switch is of major clinical relevance to the treatment of β-haemoglobinopathies, with many studies observing that clinical upregulation of the fetal γ-globin in adulthood can ameliorate the severity of these diseases.
Histone modifications have long been understood to be key players in globin switching, with initial evidence of histone lysine methylation correlating with gene expression in the chicken β-globin locus over two decades ago. This importance is conserved across species, with numerous studies of the mouse and human locus over the years producing similar findings. However, most of this work was done using cell lines that express high levels of fetal γ-globin, which have hampered efforts to explore the importance of histone modifications in reactivating fetal γ-globin expression.
In the last decade, erythroid cell lines have been generated that express adult globins, including HUDEP2 and BEL-A cells, which have allowed us to investigate how histone modifications might be able to be manipulated to reactivate fetal γ-globin expression. Only a handful of studies have investigated histone marks, all of which have been performed in HUDEP2s. As of yet, no study has been performed systematically comparing the histone landscape in these adult-like red blood cell lines.
Using ChIP-seq, we plan to map a range of histone marks in both HUDEP2 and BEL-A cells. An in-depth characterisation of the differences in histone landscape between these cells could provide important direction for further epigenetic therapies for β-haemoglobinopathies.