Globin gene regulation and switching: circa 1990.

Suggestions that the field of hemoglobin regulation and erythroid cell molecular biology was undergoing a tortuous and slow death, awash in the scientific community several years ago, were dispelled by the findings presented at the Seventh Conference on Hemoglobin Switching. After a phase in which neither the cis-elements nor trans-factors important for globin and erythroid gene expression were evident, recent progress has been rapid. Once again, studies in this area are providing fundamental insights into eukaryotic biology. The long-distance influence of LCR elements on chromatin structure and gene expression is remarkable and likely to be encountered in the analysis of other developmentally regulated, multigene loci. How LCR elements influence chromatin structure and maintain an open configuration is a problem at the core of gene regulation. We can be optimistic that further dissection of LCRs will delineate DNA sequences critical for these effects and associated proteins. The interaction of LCRs with individual genes must depend on specific protein-protein interactions, most likely involving a small, but elite, group of regulators. At least one critical transcriptional regulator of erythroid-expressed genes, GATA-1, is firmly established. Others are being pursued. The mechanisms by which they collaborate with each other should provide the missing pieces to the puzzle of cell-specific gene expression in the erythroid lineage. As the phenomenology of Hb switching is mimicked in transgenic mice, the elements mediating competitive and non-competitive (or autonomous) modes of regulation will be systematically delineated. Whether knowledge of the cis- and trans- components involved in switching will lead to the development of therapeutic approaches aimed at altering their complex interactions is uncertain. Fortunately, recent progress in hematopoietic stem cell biology once again raises hopes that gene transfer strategies for management of hemoglobin disorders may be more than a distant, impractical goal.