Gene order in human alpha-globin locus is required for their temporal specific expressions.
The human alpha-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 zeta- and fetal/adult alpha-genes to their distal regulatory element alpha-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 alpha-globin locus in a BAC clone bringing alpha-genes closest to alpha-URE and zeta-gene the farthest away. Expression analysis of the reverted locus in transgenic mice showed that alpha-globin genes, now relocated closer to alpha-URE, maintained their expression levels through all developmental stages. However, the zeta-globin gene suffered a total loss at both embryonic and fetal/adult stages. It indicates that proximal location of zeta-globin gene to alpha-URE is necessary for its normal embryonic expression and necessary to prevent embryonic expression of the alpha-globin gene. We proved that, in the human alpha-globin gene cluster, the normal order of structural genes relative to alpha-URE plays a crucial role in the regulation of developmental switching.
Tang
Yi
Y
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.
Wang
Zhao
Z
Huang
Yue
Y
Liu
De-pei
DP
Liu
Guang
G
Shen
Wei
W
Tang
Xiaobin
X
Feng
Dongxiao
D
Liang
Chih-chuan
CC
D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D023061:Gene Order / Q000235:genetics*; D005914:Globins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015183:Restriction Mapping; D013997:Time Factors
D005914:Globins