Regulation

The globin gene clusters contain several types of regulatory elements that interact to promote erythroid-specific gene expression and to coordinate changes in globin gene activity during development. They include promoter elements, enhancers, i.e. regulatory elements that increase gene expression despite being located at a variable distance from the genes, and, in the case of the P-globin gene cluster, a master sequence called the 'locus control region' (LCR), or 'locus activating region' (LAR), which lies upstream from the cluster. The a-gene cluster has a homologous upstream sequence designated HS40 (HS stands for DNase 1 hypersensitive site, which is characteristic of these regions). Each of these sequences has a modular structure made up of an array of short motifs that represent the binding sites for transcrip-tional activators or repressors.

The regulation of globin gene expression is mediated at several levels; although most occurs at the transcriptional level, there is some fine-tuning during and after translation. Most DNA that is not involved in gene transcription is tightly packaged into a compact, chemically modified form that is inaccessible to transcription factors and polymerases and which is heavily methylated. Activity is associated with a change in the structure of the chromatin surrounding a gene, which can be identified by enhanced sensitivity to nucleases. Erythroid lineage-specific nuclease hypersensitive sites are found at several locations in the P-globin gene cluster. Four are distributed over a 20-kb region upstream from the e-globin gene in the region of the P-globin LCR. This key regulatory region establishes a transcriptionally active domain spanning the entire P-globin gene cluster. Several enhancer sequences have been identified in this cluster. All

TA AA AA

Levels of defective function

Flanking

Transcription

Nucleus

AAAA-A

Cytoplasm

Transfer RNA

Amino \ acid

Growing chain

Processed y chain ^

Finished chain

Amino \ acid

Growing chain

Processed y chain ^

Finished chain

Processing

Initiation

Translation

Termination

Post-translational stability

Figure 6. 2 The genetic control of the synthesis of a globin chain. *Levels of action of mutations.

of these regulatory regions bind a number of erythroid-specific transcription factors, notably GATA-1 and NF-E2, as well as factors that are more ubiquitous in their tissue distribution (see Chapter 2).

The binding of haemopoietic-specific factors activates the LCR, which renders the entire P-globin gene cluster transcrip-tionally active. Transcription factors also bind to enhancer and promoter sequences, which work in tandem to regulate the expression of the individual genes in the clusters. Some of the transcription factors are developmental stage specific and may be involved in the (still poorly understood) differential expression of the embryonic, fetal and adult globin genes.

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