tailieunhanh - Báo cáo Y học: The human b-globin locus control region A center of attraction

The human b-globin gene locus is the subject of intense study, and over the past two decades a wealth of information has accumulated on how tissue-specific and stage-specific expression of its genes is achieved. The data are extensive and it would be difficult, if not impossible, to formulate a comprehensive model integrating every aspect of what is currently known. In this review, we introduce the fundamental characteristics of globin locus regulation as well as questions on which much of the current research is predicated. We then outline a hypothesis that encompasses more recent results, focusing on the modification of higher-order. | Eur. J. Biochem. 269 1589-1599 2002 FEBS 2002 REVIEW ARTICLE The human b-globin locus control region A center of attraction Padraic P. Levings and Jorg 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 and over the past two decades a wealth of information has accumulated on how tissue-specifc and stage-specifc expression of its genes is achieved. The data are extensive and it would be difficult if not impossible to formulate a comprehensive model integrating every aspect of what is currently known. In this review we introduce the fundamental characteristics of globin locus regulation as well as questions on which much of the current research is predicated. We then outline a hypothesis that encompasses more recent results focusing on the modifcation 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 chromatinmodifying 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 transcription complexes to globin gene promoters. Keywords chromatin domains globin genes intergenic transcription locus control region transcription. ORGANIZATION AND STRUCTURE OF THE HUMAN b-GLOBIN LOCUS The five genes of the human b-globin locus are arranged in a linear array on chromosome 11 and