THE COMPLETE SEQUENCES OF THE GALAGO AND RABBIT BETA-GLOBIN LOCUS-CONTROL REGIONS - EXTENDED SEQUENCE AND FUNCTIONAL CONSERVATION OUTSIDE THE CORES OF DNASE HYPERSENSITIVE SITES

The locus control region (LCR) of mammalian beta-globin genes covers a t least 17 kb at the 5' end of the gene cluster and has been implicate d in chromatin domain opening, enhancement, and insulation hom neighbo ring sequences. Functional dissection of the LCR has defined the minim al cores for four of the five major DNase hypersensitive sites (HSs) t hat mark this regulatory region. To examine? fully the patterns of con served sequences in the mammalian homologs to the beta-globin LCR, we determined the complete DNA sequence of the galago beta-globin LCR and completed previously unsequenced regions of the rabbit LCR Simultaneo us alignment of these sequences with the human, goat, and mouse LCRs r evealed conserved sequences (phylogenetic footprints) detected using t hree largely independent methods. The most highly conserved segments a re found both within the HS cores and in some but not all regions flan king the cores. These results argue for an extended pattern of well-co nserved sequences, many of which lie outside the minimal cores, and we show that a key sequence required for domain opening by the region in cluding HS3 maps about 1 kb 5' to the minimal core. Differential phylo genetic footprints, containing sequences conserved in nonhuman mammals but not in humans, are found primarily around HS3, consistent with so me species-specific differences in function that may be important for differences in hemoglobin switching during development. (C) 1997 Acade mic Press