Beyond the locus control region: new light on beta-globin locus regulation

The locus control region (LCR) is a novel class of cis-acting regulatory sequences that enable high-level, tissue-specific, copy number-dependent, and chromosomal position-independent gene expression in transgenic mice. Recent studies on endogenous beta-globin locus and other loci have offered new insights either in support of or in contrast to our knowledge of the relationship between chromatin conformation and transcriptional regulation, the long-distance interaction between enhancers and promoters, and the developmental switching of multiple-gene loci. Our perceptions of the regulatory roles for LCR and elements beyond the LCR in beta-globin locus regulation have been challenged and demand re-evaluation. A sound elucidation of gene regulation mechanisms may rely on a fine understanding of functional interplay between cis-acting elements and trans-acting factors that participate in gene silencing and activation in their native genomic, cellular, and developmental state.