Switching from fetal to adult hemoglobin

Abstract

The switch from fetal to adult hemoglobin relies on repression or silencing of the upstream γ-globin gene, but identification of the transcriptional repressors that bind to the sites at which a cluster of naturally occurring variants associated with HPFH (hereditary persistence of fetal hemoglobin) are found has been elusive. A new study provides mechanistic evidence for the direct binding of BCL11A and ZBTB7A, two previously identified γ-globin gene repressors.

Fig. 1 |. Point mutations in γ-globin gene promoters disrupt binding of transcriptional repressors, resulting in elevated fetal hemoglobin levels in adulthood.

BCL11A and ZBTB7A bind to the γ-globin promoter in two sites with clustered mutations in HPFH and inhibit expression. However, individuals with HPFH-associated mutations have a mutated consensus sequence for BCL11A and/or ZBTB7A binding, de-repressing fetal hemoglobin expression during adulthood. The consensus sequences for BCL11A and ZBTB7A binding are shown in red. The HPFH-associated mutations in the cluster (inverted arrows) at −200 bp, from left to right, are c.−202C>T/G, c.−201C>T, c.−197C>T, c.−196C>T and c.−195C>G; the HPFH-associated mutations (upward arrows) in the cluster at −115 bp, from left to right, are c.−117G>A and c.−114C>T/A/G.