The murine beta-globin locus control region regulates the rate of transcription but not the hyperacetylation of histones at the active genes

Locus control regions (LCRs) are defined by their ability to confer high-le vel tissue-specific expression to linked genes in transgenic assays. Previo usly, we reported that, at its native site, the murine beta -globin LCR is required for high-level beta -globin gene expression, but is not required t o initiate an open chromatin conformation of the locus. To further investig ate the mechanism of LCR-mediated transcriptional enhancement, we have anal yzed allele-specific beta -globin expression and the pattern of histone ace tylation in the presence and absence of the LCR. In single cells from mice heterozygous for a deletion of the LCR, beta -globin expression from the LC R-deleted allele is consistently low (approximate to1-4% of wild type). Thu s, the endogenous LCR enhances globin gene expression by increasing the rat e of transcription from each linked allele rather than by increasing the pr obability of establishing transcription per se. Furthermore, in erythroid c ells from mice homozygous for the highly expressing wild-type beta -globin locus, hyperacetylation of histones H3 and H4 is localized to the LCR and a ctive genes. In mice homozygous for the LCR deletion reduced histone hypera cetylation is observed in LCR proximal sequences; however, deletion of the LCR has no effect on the localized hyperacetylation of the genes. Together, our results suggest that, in its native genomic context, the LCR follows t he rate model of enhancer function, and that the developmentally specific h yperacetylation of the globin genes is independent of both the rate of tran scription and the presence of the LCR.