The role of p22 NF-E4 in human globin gene switching.
The human stage selector protein, a complex containing the ubiquitous transcription factor CP2 and the erythroid-specific factor p22 NF-E4, facilitates the interaction of the gamma-globin genes with the locus control region in fetal erythroid cells. Enforced expression of p22 NF-E4 in K562 cells and human cord blood progenitors increases fetal globin gene expression, and in progenitors, reduces beta-globin expression. To examine the role of NF-E4 in an in vivo model of hemoglobin switching, we enforced the expression of p22 NF-E4 in transgenic mice carrying the human beta-globin locus yeast artificial chromosome. Although murine erythropoiesis and globin gene expression is unaffected in these mice, the expression profile of the human globin genes is altered. All three transgenic lines displayed an increased gamma:beta-globin ratio in E12.5-14.5 fetal liver, resulting in a delay in the fetal/adult switch. At E12.5, this is primarily due to a reduction of beta-gene expression, whereas at E14.5, the increased gamma:beta ratio is due to enhanced gamma-gene expression. Despite this, the switch in globin subtype is fully completed in the adult bone marrow. These findings indicate that p22 NF-E4 is capable of influencing human globin gene expression in vivo but is incapable of overriding the intrinsic mechanisms governing gamma-gene silencing in this context.
Zhou
Wenlai
W
Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville VIC, 3050 Australia.
Zhao
Quan
Q
Sutton
Rosemary
R
Cumming
Helen
H
Wang
Xi
X
Cerruti
Loretta
L
Hall
Mark
M
Wu
Ruiqiong
R
Cunningham
John M
JM
Jane
Stephen M
SM
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D018244:Chromosomes, Artificial, Yeast / Q000378:metabolism; D003062:Codon; D018076:DNA, Complementary / Q000378:metabolism; D000939:Epitopes; D004920:Erythropoiesis; D005312:Fetal Blood / Q000378:metabolism; D005812:Genes, Switch; D005914:Globins / Q000737:chemistry*; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D017578:Immunoglobulin Class Switching; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D019076:Transgenes
D003062:Codon; D018076:DNA, Complementary; D000939:Epitopes; D006454:Hemoglobins; D014157:Transcription Factors; C063115:enhancer-binding protein NF-E4; C487821:transcription factor NF-E4, human; D005914:Globins