Regulation of human fetal hemoglobin: new players, new complexities

Abstract

The human globin genes are among the most extensively characterized in the human genome, yet the details of the molecular events regulating normal human hemoglobin switching and the potential reactivation of fetal hemoglobin in adult hematopoietic cells remain elusive. Recent discoveries demonstrate physical interactions between the beta locus control region and the downstream structural gamma- and beta-globin genes, and with transcription factors and chromatin remodeling complexes. These interactions all play roles in globin gene expression and globin switching at the human beta-globin locus. If the molecular events in hemoglobin switching were better understood and fetal hemoglobin could be more fully reactivated in adult cells, the insights obtained might lead to new approaches to the therapy of sickle cell disease and beta thalassemia by identifying specific new targets for molecular therapies.

Figure 1.

The human β-globin locus. (A) The β-globin locus on chromosome 11 embedded in chromatin is shown. (B) A linear map with the globin LCR and its hypersensitive (HS) sites is indicated by the vertical arrows. The structural ε-, γ-, δ-, and β-globin genes as well as the locations of the olfactory receptor (OR) genes are shown.

Figure 2.

Mutations and the extent of deletion in thalassemias and HPFH. A × indicates point mutation. Dotted lines indicate deletions. There is more deletion of γ-δ intergenic sequences in HPFH than in δ-β thalassemia, and the 3′ extent of the deletion is greater in HPFH.

Figure 3.

The proposed role of the PYR complex in human hemoglobin switching. The circles indicate unspecified chromatin remodeling complexes and transcription factors. The details of these interactions in chromatin between the βLCR elements, globin structural genes, erythroid transcription factors, and these chromatin remodeling complexes are unknown. In fetal-embryonic cells, the human βLCR is associated with the γ-globin gene loci downstream. The blue circles include the potential activities of FKLF and SSP in this process at the γ-globin promoter. In adult-type cells, the βLCR associates with and activates β-globin gene expression. New interactions leading to repression of γ-globin gene expression occur, and PYR complex binding and its HDACs may contribute to this process. The SWI/SNF complex subunits, the NURD subunits, and the DNA-binding subunit Ikaros of the PYR complex are shown.