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rdf:type |
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lifeskim:mentions |
umls-concept:C0001721,
umls-concept:C0017033,
umls-concept:C0019025,
umls-concept:C0025936,
umls-concept:C0031437,
umls-concept:C0086860,
umls-concept:C1167622,
umls-concept:C1333663,
umls-concept:C1442824,
umls-concept:C1530719,
umls-concept:C1533691,
umls-concept:C1555721,
umls-concept:C1706204
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pubmed:issue |
9
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pubmed:dateCreated |
2005-2-28
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pubmed:abstractText |
The T to C substitution at position -175 of the gamma-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 mu'LCRAgamma(-175)psibetadeltabeta construct, which contained a 3.1-kb mu'LCR cassette linked to a 29-kb fragment from the Agamma-to beta-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 mu'LCRAgamma(-173)psibetadeltabeta construct, in which the -175 T to C Agamma gene was substituted with the -173 T to C Agamma 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 gamma-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 gamma-globin gene in adult erythrocytes.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Chromatin,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Erythroid-Specific DNA-Binding...,
http://linkedlifedata.com/resource/pubmed/chemical/GATA1 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/GATA1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Gata1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Globins,
http://linkedlifedata.com/resource/pubmed/chemical/Octamer Transcription Factor-1,
http://linkedlifedata.com/resource/pubmed/chemical/POU2F1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Pou2f1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/RNA,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
4
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7452-9
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:15613485-Animals,
pubmed-meshheading:15613485-Base Sequence,
pubmed-meshheading:15613485-Binding Sites,
pubmed-meshheading:15613485-Cell Line, Tumor,
pubmed-meshheading:15613485-Chromatin,
pubmed-meshheading:15613485-Chromatin Immunoprecipitation,
pubmed-meshheading:15613485-Cosmids,
pubmed-meshheading:15613485-DNA,
pubmed-meshheading:15613485-DNA-Binding Proteins,
pubmed-meshheading:15613485-Erythrocytes,
pubmed-meshheading:15613485-Erythroid-Specific DNA-Binding Factors,
pubmed-meshheading:15613485-GATA1 Transcription Factor,
pubmed-meshheading:15613485-Gene Deletion,
pubmed-meshheading:15613485-Gene Expression Regulation,
pubmed-meshheading:15613485-Gene Expression Regulation, Developmental,
pubmed-meshheading:15613485-Globins,
pubmed-meshheading:15613485-HeLa Cells,
pubmed-meshheading:15613485-Humans,
pubmed-meshheading:15613485-K562 Cells,
pubmed-meshheading:15613485-Mice,
pubmed-meshheading:15613485-Mice, Transgenic,
pubmed-meshheading:15613485-Models, Genetic,
pubmed-meshheading:15613485-Molecular Sequence Data,
pubmed-meshheading:15613485-Mutation,
pubmed-meshheading:15613485-Octamer Transcription Factor-1,
pubmed-meshheading:15613485-Phenotype,
pubmed-meshheading:15613485-Plasmids,
pubmed-meshheading:15613485-Point Mutation,
pubmed-meshheading:15613485-Polymerase Chain Reaction,
pubmed-meshheading:15613485-Promoter Regions, Genetic,
pubmed-meshheading:15613485-Protein Binding,
pubmed-meshheading:15613485-Protein Conformation,
pubmed-meshheading:15613485-RNA,
pubmed-meshheading:15613485-RNA, Messenger,
pubmed-meshheading:15613485-Time Factors,
pubmed-meshheading:15613485-Transcription Factors
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pubmed:year |
2005
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pubmed:articleTitle |
T to C substitution at -175 or -173 of the gamma-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.
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pubmed:affiliation |
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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