LOCUS-CONTROL REGIONS OF MAMMALIAN BETA-GLOBIN GENE CLUSTERS - COMBINING PHYLOGENETIC ANALYSES AND EXPERIMENTAL RESULTS TO GAIN FUNCTIONAL INSIGHTS

Locus control regions (LCRs) are cis-acting DNA segments needed for ac tivation of an entire locus or gene cluster. They are operationally de fined as DNA sequences needed to achieve a high level of gene expressi on regardless of the position of integration in transgenic mice or sta bly transfected cells. This review brings together the large amount of DNA sequence data from the beta-globin LCR with the vast amount of fu nctional data obtained through the use of biochemical, cellular and tr ansgenic experimental systems. Alignment of orthologous LCR sequences from five mammalian species locates numerous conserved regions, includ ing previously identified cis-acting elements within the cores of nucl ease hypersensitive sites (HSs) as well as conserved regions located b etween the HS cores. The distribution of these conserved sequences, co mbined with the effects of LCR fragments utilized in expression studie s, shows that important sites are more widely distributed in the LCR t han previously anticipated, especially in and around HS2 and HS3. We p ropose that the HS cores plus HS flanking DNAs comprise a 'unit' to wh ich proteins bind and form an optimally functional structure. Multiple HS units (at least three: HS2, HS3 and HS4 cores plus flanking DNAs) together establish a chromatin structure that allows the proper develo pmental regulation of genes within the cluster. (C) 1997 Elsevier Scie nce B.V.