Epigenetics of beta-globin gene regulation

Abstract

It is widely recognized that the next great challenge in the post-genomic period is to understand how the genome establishes the cell and tissue specific patterns of gene expression that underlie development. The beta-globin genes are among the most extensively studied tissue specific and developmentally regulated genes. The onset of erythropoiesis in precursor cells and the progressive expression of different members of the beta-globin family during development are accompanied by dramatic epigenetic changes in the locus. In this review, we will consider the relationship between histone and DNA modifications and the transcriptional activity of the beta-globin genes, the dynamic changes in epigenetic modifications observed during erythroid development, and the potential these changes hold as new targets for therapy in human disease.

Figure 1

Hemoglobin switching and hemoglobins produced during development. The globin genes of the human α and β-globin loci are indicated by the colored block arrows that also represent the direction of transcription of the genes. The horizontal arrows above represent a switching event leading to expression of the next, downstream gene in the locus. Below the depiction of the loci, the various hemoglobin tetramers produced at each developmental stage in erythroid cells of humans are indicated along with their globin polypeptide composition.

Figure 2

Long range chromatin looping in the β-globin locus. (A) The human β-globin locus is depicted with the LCR hypersensitive sites marked by downward arrows and the structural genes denoted by colored block arrow that indicate the direction of transcription of the genes. (B) The globin locus LCR and adult β-globin gene come in to close proximity in adult stage erythroid cells in which that gene is actively transcribed [16, 17]. The embryonic and fetal expressed genes that are silent at this stage of development are excluded from the close contacts. The looping interactions are developmentally regulated [48].

Figure 3

Structural organization of vertebrate β-globin genes. The β-globin genes of the chicken, mouse and human loci are represented by colored block arrows. The LCR DHSs are indicated by black arrows and the locus flanking, non-tissues specific DHSs are indicated by red arrows. FR, folate receptor gene, HSA, a DHS in the chicken locus associated with transcription of the FR, ORGs, odorant receptor genes not expressed in erythroid cells. The grey, striped rectangle represents a region of heterochromatin upstream of the LCR in chicken erythroid cells. The grey boxes under the loci represent the extents of HS5 or 3′HS1 deletions referred to in the text and are followed by the appropriate citation in brackets.

Figure 4

Chromatin insulator function. (A) Insulator barrier. An insulator (red striped octagon) is depicted between a region of silent, hypo-acetylated chromatin featuring the H3K9 methylation mark and a region of active, hyper-acetylated chromatin marked by H3K4 methylation. The insulator is proposed to oppose the encroachment of the silent chromatin into the active region. Close-packed nucleosomes are depicted in grey and those that are loosely packed in green. (B) Enhancer blocker. Enhancer B can activate gene B but the insulator blocks enhancer A from activating gene B. Under these conditions, enhancer A can still activate gene A from which it is not blocked. The insulator is proposed to block a signal from an enhancer to a gene.

Figure 5

Changes in epigenetic modification of the human β-globin locus during development. The β-globin genes of the human locus are represented by colored block arrows. The LCR DHSs are indicated by black arrows and the locus flanking, non-tissues specific DHSs are indicated by red arrows. Domains of histone acetylation and H3K4 di-methylation are depicted by colored shapes (magnitude not drawn to scale) below the locus at different stages of development. The patterns are consistent with or implied by data from several laboratories [12, 23, 57]. Epigenetic modifications in the mouse locus are, overall, similar [50, 70]. Some data support the reciprocal presence of H3 K9 methylation at the adult genes before they are activated [12, 73]. ORGs, odorant receptor genes