Swee Lay Thein
King’s College London / King’s College NHS Foundation Trust, London, UK
The switch from fetal (HbF, α2γ2) to adult haemoglobin (HbA, α2β2) production in humans, occurs around birth but it is not complete. The residual amounts of HbF that continue to be produced throughout adult life varies considerably by >30-fold. Persistence of fetal haemoglobin levels have no consequence in healthy adults but have a major impact on the severity of β thalassaemia and sickle cell disease (SCD), diseases with substantial morbidity and mortality worldwide. Clinical and twin studies have shown that inter-individual HbF variation is largely genetically controlled. Our understanding of haemoglobin control, including the persistence of HbF synthesis in adults, historically has been based on Mendelian models of inheritance of natural mutants. Indeed, characterisation of a series of mutations associated with increased HbF levels, the pancellular hereditary persistence of fetal haemoglobin (HPFH), and δβ thalassaemia, have been invaluable in deriving our current understanding of the switch from fetal to adult haemoglobin – gene competition and autonomous silencing mediated by transcription factors. Identification of these transcription factors have eluded us until recently. Dawn of the “..omics” era using genetic, genomic, transcriptomic and proteomic approaches have provided new insights into the developmental regulation of the fetal and adult globin genes and identified specific transcription factors and epigenetic regulators modulating the switch underlying the common variation in HbF levels in adults. These transcription factors (BCL11A, KLF1, and MYB ) and chromatin modifiers (histone deacetylases, DNA methyltransferases, and nuclear receptors TR2/TR4) are attractive molecular targets for therapeutic induction of fetal haemoglobin. As always, however, substantial hurdles remain in achieving specificity of effect and adequate therapeutic window. Achievement of optimal therapeutic induction may well involve a combination of different strategies and molecular targets.