Differential requirement of a distal regulatory region for pre-initiation complex formation at globin gene promoters.
Although distal regulatory regions are frequent throughout the genome, the molecular mechanisms by which they act in a promoter-specific manner remain to be elucidated. The human beta-globin locus constitutes an extremely well-established multigenic model to investigate this issue. In erythroid cells, the beta-globin locus control region (LCR) exerts distal regulatory function by influencing local chromatin organization and inducing high-level expression of individual beta-like globin genes. Moreover, in transgenic mice expressing the entire human beta-globin locus, deletion of LCR-hypersensitive site 2 (HS2) can alter beta-like globin gene expression. Here, we show that abnormal expression of human beta-like globin genes in the absence of HS2 is associated with decreased efficacy of pre-initiation complex formation at the human epsilon- and gamma-promoters, but not at the beta-promoter. This promoter-specific phenomenon is associated with reduced long-range interactions between the HS2-deleted LCR and human gamma-promoters. We also find that HS2 is dispensable for high-level human beta-gene transcription, whereas deletion of this hypersensitive site can alter locus chromatin organization; therefore the functions exerted by HS2 in transcriptional enhancement and locus chromatin organization are distinct. Overall, our data delineate one mechanism whereby a distal regulatory region provides promoter-specific transcriptional enhancement.
Ross
Julie
J
Faculty of Medicine, University of Montreal, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada.
Bottardi
Stefania
S
Bourgoin
Vincent
V
Wollenschlaeger
Alex
A
Drobetsky
Elliot
E
Trudel
Marie
M
Milot
Eric
E
D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism; D015870:Gene Expression; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015017:Yolk Sac / Q000166:cytology
D002843:Chromatin; D014157:Transcription Factors; D005914:Globins