Effect of fetal hemoglobin-stimulating medicines on the interaction of DNA and protein of important erythroid regulatory elements.
Beta-Thalassemia is the most common single gene disorder in the world, which is caused by the imbalance between alpha-globin chain and beta-globin chain synthesis. Several medicines, such as 5-azacytidine, hydroxyurea, cytarabine, vinblatine, butyrate, and myleran, have been shown to be able to reactivate gamma-globin chain synthesis during the adult stage, and some of them (5-azacytidine, hydroxyurea, myleran, and butyrate) have been used clinically to treat thalassemia and sickle cell disease. Much research efforts are focusing on the determination of the underlying mechanisms of medicine action. In this experiment, as an effort to probe the underlying mechanism of medicine action, we used ligation-mediated polymerase chain reaction and in vivo footprinting methods to study the DNA-protein interaction at critical erythroid regulatory elements after hydroxyurea or myleran administration to mice. Our results showed that the patterns of in vivo footprints at both the hypersensitive site 2 of the locus control region and the beta-globin gene promoter were changed after medicine treatment. We proposed based on these results that the medicines' administration might result in a change in the interaction between trans-acting factors and cis-acting elements at these regions. These changes might influence the assembly of the transcription complex and, lastly, influence the expression of the beta-globin gene.
Ji
Xin-Jun
XJ
National Library of Medicine Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Faculty of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China.
Liu
De-pei
DP
Xu
Dong-Dong
DD
Li
Lei
L
Liang
Chih-chuan
CC
D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology*; D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism*; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000378:metabolism*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000187:drug effects*; D005914:Globins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D017086:beta-Thalassemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D000986:Antisickling Agents; D004268:DNA-Binding Proteins; D005914:Globins; D005319:Fetal Hemoglobin