Mutation of gene-proximal regulatory elements disrupts human ɛ- γ- and β-globin expression in yeast artificial chromosome transgenic mice

摘要

Previous studies have defined transcriptional control elements, in addition to the promoters, that both lie near individual human β-globin locus genes and have been implicated in their differential stage-specific regulation during development (i.e., are believed to directly participate in hemoglobin switching). We have reinvestigated the activities during erythropoiesis that might be conferred by two of the more intensively analyzed of these elements, the ɛ-globin gene 5′ silencer and the β-globin gene 3′ enhancer, by deleting them from a yeast artificial chromosome that spans the human β-globin locus, and then analyzing transgenic mice for expression of all of the human genes. These studies show that sequences within the ɛ-globin “silencer” are not only required for silencing but are also required for activation of ɛ-globin transcription; furthermore, deletion of the silencer simultaneously reduced γ-globin transcription during the yolk sac stage of erythroid development. Analysis of the adult β-globin gene 3′ enhancer deletion showed that its deletion affects only that gene.