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Unformatted text preview: REVIEW ARTICLE The human b-globin locus control region A center of attraction Padraic P. Levings and Jo rg Bungert Department of Biochemistry and Molecular Biology, Gene Therapy Center, Center for Mammalian Genetics, College of Medicine, University of Florida, Gainesville, FL, USA The human b-globin gene locus is the subject of intense study,andoverthepasttwodecadesawealthofinformation has accumulated on how tissue-specific and stage-specific expressionofitsgenesisachieved.Thedataareextensiveand it would be difficult, if not impossible, to formulate a com- prehensive model integrating every aspect of what is cur- rently known. In this review, we introduce the fundamental characteristics of globin locus regulation as well as questions onwhichmuchofthecurrentresearchispredicated.Wethen outline a hypothesis that encompasses more recent results, focusing on the modification of higher-order chromatin structure and recruitment of transcription complexes to the globin locus. The essence of this hypothesis is that the locus control region (LCR) is a genetic entity highly accessible to and capable of recruiting, with great efficiency, chromatin- modifying, coactivator, and transcription complexes. These complexes are used to establish accessible chromatin domains, allowing basal factors to be loaded on to specific globin gene promoters in a developmental stage-specific manner. We conceptually divide this process into four steps: (a) generation of a highly accessible LCR holocomplex; (b) recruitment of transcription and chromatin-modifying complexes to the LCR; (c) establishment of chromatin domains permissive for transcription; (d) transfer of tran- scription complexes to globin gene promoters. Keywords : chromatin domains; globin genes; intergenic transcription; locus control region; transcription. O R G A N I Z A T I O N A N D S T R U C T U R E O F T H E H U M A N b-G L O B I N L O C U S The five genes of the human b-globin locus are arranged in a linear array on chromosome 11 and are expressed in a developmental stage-specific manner in erythroid cells (Fig. 1) . The e-globin gene is transcribed in the embry- onic yolk sac and located at the 5 end. After the switch in the site of hematopoiesis from the yolk sac to the fetal liver, the e-gene is repressed and the two c-globin genes, located downstream of e , are activated. In a second switch, completed shortly after birth, the bone marrow becomes the major site of hematopoiesis, coincident with activation of the adult b-globin gene, while the c-globin genes become silenced. The d-globin gene is also activated in erythroid cells derived from bone marrow hematopoiesis but is only expressed at levels less than 5% of that of the b-globin gene....
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