Defective erythropoiesis in transgenic mice expressing dominant-negative upstream stimulatory factor.
Transcription factor USF is a ubiquitously expressed member of the helix-loop-helix family of proteins. It binds with high affinity to E-box elements and, through interaction with coactivators, aids in the formation of transcription complexes. Previous work demonstrated that USF regulates genes during erythroid differentiation, including HoxB4 and beta-globin. Here, we show that the erythroid cell-specific expression of a dominant-negative mutant of USF, A-USF, in transgenic mice reduces the expression of all beta-type globin genes and leads to the diminished association of RNA polymerase II with locus control region element HS2 and with the beta-globin gene promoter. We further show that the expression of A-USF reduces the expression of several key erythroid cell-specific transcription factors, including EKLF and Tal-1. We provide evidence demonstrating that USF interacts with known regulatory DNA elements in the EKLF and Tal-1 gene loci in erythroid cells. Furthermore, A-USF-expressing transgenic mice exhibit a defect in the formation of CD71(+) progenitor and Ter-119(+) mature erythroid cells. In summary, the data demonstrate that USF regulates globin gene expression indirectly by enhancing the expression of erythroid transcription factors and directly by mediating the recruitment of transcription complexes to the globin gene locus.
Liang
Shermi Y
SY
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Moghimi
Babak
B
Crusselle-Davis
Valerie J
VJ
Lin
I-Ju
IJ
Rosenberg
Michael H
MH
Li
Xingguo
X
Strouboulis
John
J
Huang
Suming
S
Bungert
Jörg
J
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002645:Chickens; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000235:genetics*; D055544:beta-Globins / Q000235:genetics
D015703:Antigens, CD; C068126:CD71 antigen; D011990:Receptors, Transferrin; D014157:Transcription Factors; D051720:Upstream Stimulatory Factors; D055544:beta-Globins; D012319:RNA Polymerase II
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