HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 9, 7452-7459, March 4, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/9/7452    most recent M411407200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, L.-R. Articles by Zhang, J.-W. Search for Related Content PubMed PubMed Citation Articles by Liu, L.-R. Articles by Zhang, J.-W. Social Bookmarking                      What's this?

T to C Substitution at –175 or –173 of the -Globin Promoter Affects GATA-1 and Oct-1 Binding in Vitro Differently but Can Independently Reproduce the Hereditary Persistence of Fetal Hemoglobin Phenotype in Transgenic Mice^*

Li-Ren Liu, Zhan-Wen Du, Hua-Lu Zhao, Xiao-Ling Liu, Xiao-Dong Huang, Jie Shen, Li-Mei Ju, Fu-De Fang, and Jun-Wu Zhang¶

From the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China and Institute of Experimental Animals, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

The T to C substitution at position –175 of the -globin gene has been identified in some individuals with non-deletion hereditary persistence of fetal hemoglobin (HPFH). In this study, the HPFH phenotype was reestablished in transgenic mice carrying the µ'LCRA^–175 construct, which contained a 3.1-kb µ'LCR cassette linked to a 29-kb fragment from the A-to -globin gene with the natural chromosome arrangement but with the –175 mutation, which provided evidence for this single mutation as the cause of this form of HPFH. The HPFH phenotype was also reproduced in transgenic mice carrying the µ'LCRA^–173 construct, in which the –175 T to C A gene was substituted with the –173 T to C A gene. In vitro experiments proved that the –175 mutation significantly reduced binding of Oct-1 but not GATA-1, whereas the –173 mutation dramatically decreased binding of GATA-1 but not Oct-1. These results suggest that abrogation of either GATA-1 or Oct-1 binding to this promoter region may result in the HPFH phenotype. An in vivo footprinting assay revealed that either the –175 mutation or the –173 mutation significantly decreased overall protein binding to this promoter region in adult erythrocytes of transgenic mice. We hypothesize that a multiprotein complex containing GATA-1, Oct-1, and other protein factors may contribute to the formation of a repressive chromatin structure that silences -globin gene expression in normal adult erythrocytes. Both the –173 and –175 T to C substitutions may disrupt the complex assembly and result in the reactivation of the -globin gene in adult erythrocytes.

Received for publication, October 6, 2004 , and in revised form, December 20, 2004.

^* This work was supported by Grants 39893320 and 30393110 from the National Science Foundation of China (to J.-W. Z). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, China. Tel.: 86-10-65296423; Fax: 86-10-65240529; E-mail: junwu_zhang{at}pumc.edu.cn.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Bianchi, C. Zuccato, I. Lampronti, M. Borgatti, and R. Gambari Fetal Hemoglobin Inducers from the Natural World: A Novel Approach for Identification of Drugs for the Treatment of -Thalassemia and Sickle-Cell Anemia Evid. Based Complement. Altern. Med., December 11, 2007; (2007) nem139v1. [Abstract] [Full Text] [PDF]

				I. A. Olave, C. Doneanu, X. Fang, G. Stamatoyannopoulos, and Q. Li Purification and Identification of Proteins That Bind to the Hereditary Persistence of Fetal Hemoglobin -198 Mutation in the {gamma}-Globin Gene Promoter J. Biol. Chem., January 12, 2007; 282(2): 853 - 862. [Abstract] [Full Text] [PDF]

				R. H. Lewinsky, T. G.K. Jensen, J. Moller, A. Stensballe, J. Olsen, and J. T. Troelsen T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro Hum. Mol. Genet., December 15, 2005; 14(24): 3945 - 3953. [Abstract] [Full Text] [PDF]