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National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College & Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Beijing, 100005, China

The human -globin cluster represents a unique model of transcriptional regulation and provides challenges to the current understanding of interactions between distal and proximal regulatory elements. Although the gene proximal regions are believed to possess almost all the necessary elements for temporal and spatial specificity of gene transcription, it is still not clear whether the relative distance of embryonic - and fetal/adult -genes to their distal regulatory element -URE plays any role in transcriptional switching. To investigate the role of gene order in regulating temporal expression, we inverted the entire structure gene region of human -globin locus in a BAC clone bringing -genes closest to -URE and -gene the farthest away. Expression analysis of the reverted locus in transgenic mice showed that -globin genes, now relocated closer to -URE, maintained their expression levels through all developmental stages. However, the -globin gene suffered a total loss at both embryonic and fetal/adult stages. It indicates that proximal location of -globin gene to -URE is necessary for its normal embryonic expression and necessary to prevent embryonic expression of the -globin gene. We proved that, in the human -globin gene cluster, the normal order of structural genes relative to -URE plays a crucial role in the regulation of developmental switching.

^* Correspondence: E-mail: liudp{at}pumc.edu.cn