Hemoglobin comes in two forms: oxyhemoglobin does not carry oxygen, can reversibly oxygenate, and carries a reduced heme iron; methemoglobin is just oxyhemoglobin that has been oxidized to carry oxygen. Methemoglobin cannot spontaneously revert to oxyhemoglobin. Methemoglobin reductase reduces methemoglobin back to oxyhemoglobin. Many hemoglobinopathies affect hemoglobin’s ability to load or unload oxygen.
Hemoglobin is composed of four subunits — two α chains (141 amino acids) and two β chains (146 amino acids) — each of which contain a polypeptide chain globin and a cofactor heme, an iron-containing chemical which binds oxygen. α2β2 hemoglobin forms a 64,500kD tetramer whose tertiary structure is extremely conserved across the animal kingdom (although only two amino acids are conserved).
The normal adult hemoglobin is hemoglobin A (HbA); the five other hemoglobin have a similar structure — two α or &alpha-like chains bound to two β or β-like chains. The α and α-like genes are clustered on chromosome 16, while the β and β-like genes are clustered on chromosome 11. The various hemoglobin are expressed at various times during development via globin switching. For example, HbA2 (α2δ2) and HbF (α2γ2) are expressed primarily during gestation.
There are four α genes and two β genes in a diploid genome. β mutations are more likely than α mutations to cause disease because each β gene accounts for half of all β chains (versus only 1/4 for each α gene). β mutations do not affect fetuses since the β-like &gamma chain is fetally expressed; however, α mutations can severely impact both fetal and postnatal life.
The locus control region (LCR) is a ∼20 kb region that is ∼6 kb upstream from the εGγAγψβδβ cluster of β and β-like genes. It contains five DNase1 hypersensitive sites, necessary to open the chromatin and allow transcription factors to activate the regulatory regions. Without the LCR, none of &epsilon, γ, ψ, δ nor β chains are expressed. The genes are expressed in the same order through development as their location on the chromosome via an unclear mechanism.
β globin locus has cis-acting elemtns in promoter and immediatel flanking regions for temporal control of β-like globin genes, but the LCR location 8 to 22kb upstream in the e-globin gene is what is needed for high level of β cluster gene expression. LCR contains at least four DNase I hypersensitive sites, provided an open chromatin domain for easy access of trnscription factos to regulatory elements in the cluster.
LCR of the alpha-globin cluster is HS-40, a DNase I hypersensitive site located 40 kb upstream of the z globin gene, is necessary for high level expression of genes in the alpha globin cluster.
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