Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching

SWI/SNF complexes in yeast and higher eukaryotes are thought to facilitate gene activation and transcription factor binding by disrupting repressive c hromatin structures, Little is known, however, about how these complexes ta rget specific genes for activation. We now have purified a specialized SWI/ SNF-related complex (PYR complex) from murine erythroleukemia (MEL) cell nu clear extract that binds pyrimidine-rich elements at the human and murine b eta-globin loci, PYR complex DNA-binding activity is restricted to definiti ve hematopoietic cells and is both DNA sequence- and length-dependent. Mass spectrometric identification of purified peptides and antibody supershift assays indicate that PYR complex contains at least four known mammalian SWI /SNF subunits: BAF57, INI1, BAF60a, and BAF170. PYR complex broadly footpri nts a 250-bp pyrimidine-rich element between the human fetal and adult beta -globin genes. A short intergenic deletion that removes this element from a human globin locus cosmid construct results in delayed human fetal-to-adul t globin gene switching in transgenic mice, Taken together, the data sugges t that PYR complex may act through this intergenic element to facilitate hu man fetal-to-adult globin gene switching, presumably by opening the locus i n the region of the adult genes to permit the binding of beta-globin transc riptional activators.