Human β-globin locus

The human β-globin locus is composed of five genes located on a short region of chromosome 11, responsible for the creation of the beta parts (roughly half) of the oxygen transport protein Haemoglobin. This locus contains not only the beta globin gene but also delta, gamma-A, gamma-G, and epsilon globin. Expression of all of these genes is controlled by single locus control region (LCR), and the genes are differentially expressed throughout development.^[1]

The order of the genes in the beta-globin cluster is: 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'.^{[citation needed]}

The arrangement of the genes directly reflects the temporal differentiation of their expression during development, with the early-embryonic stage version of the gene located closest to the LCR. If the genes are rearranged, the gene products are expressed at improper stages of development.^{[citation needed]}

Expression of these genes is regulated in embryonic erythropoiesis by many transcription factors, including KLF1,^[2] which is associated with the upregulation of adult hemoglobin in adult definitive erythrocytes, and KLF2,^[3] which is vital to the expression of embryonic hemoglobin.

HBB complex

Many CRMs have been mapped within the cluster of genes encoding β-like globins expressed in embryonic (HBE1), fetal (HBG1 and HBG2), and adult (HBB and HBD) erythroid cells. All are marked by DNase I hypersensitive sites and footprints, and many are bound by GATA1 in peripheral blood derived erythroblasts (PBDEs). A DNA segment located between the HBG1 and HBD genes is one of the DNA segments bound by BCL11A and several other proteins to negatively regulate HBG1 and HBG2. It is sensitive to DNase I but is not conserved across mammals. An enhancer located 3′ of the HBG1 gene is bound by several proteins in PBDEs and K562 cells and is sensitive to DNase I, but shows almost no signal for mammalian constraint.^[4]

References

1. Levings PP, Bungert J (Mar 2002). "The human beta-globin locus control region". European Journal of Biochemistry. 269 (6): 1589–99. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.
2. Hodge D, Coghill E, Keys J, Maguire T, Hartmann B, McDowall A, Weiss M, Grimmond S, Perkins A (Apr 2006). "A global role for EKLF in definitive and primitive erythropoiesis". Blood. 107 (8): 3359–70. doi:10.1182/blood-2005-07-2888. PMC 1895762. PMID 16380451.
3. Basu P, Morris PE, Haar JL, Wani MA, Lingrel JB, Gaensler KM, Lloyd JA (Oct 2005). "KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo". Blood. 106 (7): 2566–2571. doi:10.1182/blood-2005-02-0674. PMC 1895257. PMID 15947087.
4. Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, Ward LD, Birney E, Crawford GE, Dekker J, Dunham I, Elnitski LL, Farnham PJ, Feingold EA, Gerstein M, Giddings MC, Gilbert DM, Gingeras TR, Green ED, Guigo R, Hubbard T, Kent J, Lieb JD, Myers RM, Pazin MJ, Ren B, Stamatoyannopoulos JA, Weng Z, White KP, Hardison RC (Apr 2014). "Defining functional DNA elements in the human genome". Proceedings of the National Academy of Sciences of the United States of America. 111 (17): 6131–8. Bibcode:2014PNAS..111.6131K. doi:10.1073/pnas.1318948111. PMC 4035993. PMID 24753594.

Further reading

• Frischknecht H, Dutly F (Mar 2007). "A 65 bp duplication/insertion in exon II of the beta globin gene causing beta0-thalassemia". Haematologica. 92 (3): 423–4. doi:10.3324/haematol.10785. PMID 17339197.
• Giardina B, Messana I, Scatena R, Castagnola M (1995). "The multiple functions of hemoglobin". Critical Reviews in Biochemistry and Molecular Biology. 30 (3): 165–96. doi:10.3109/10409239509085142. PMID 7555018.
• Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ (Apr 1989). "A review of the molecular genetics of the human alpha-globin gene cluster". Blood. 73 (5): 1081–104. doi:10.1182/blood.V73.5.1081.1081. PMID 2649166.
• Salzano AM, Carbone V, Pagano L, Buffardi S, De RC, Pucci P (Feb 2002). "Hb Vila Real [beta36(C2)Pro→His] in Italy: characterization of the amino acid substitution and the DNA mutation". Hemoglobin. 26 (1): 21–31. doi:10.1081/HEM-120002937. PMID 11939509. S2CID 40757080.