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The Wsh, W57, and Ph Kit Expression Mutations Define Tissue-Specific Control Elements Located Between −23 and −154 kb Upstream of Kit

Authors :
Berrozpe, Georgina
Timokhina, Inna
Yukl, Steven
Tajima, Youichi
Ono, Masao
Zelenetz, Andrew D.
Besmer, Peter
Source :
Blood; October 1999, Vol. 94 Issue: 8 p2658-2666, 9p
Publication Year :
1999

Abstract

The Kit and PDGFRa receptor tyrosine kinases are encoded in close proximity at the murine white spotting (W) and patch (Ph) loci. Whereas W mutations affect hematopoiesis, melanogenesis, and gametogenesis, the Ph mutation affects melanogenesis and causes early lethality in homozygotes. TheWsh, W57, and Phmutations diminish Kit expression in certain cell types such as mast cells and enhance it in others. The Wsh,W57, and Ph mutations arose from deletions and inversions affecting sequences in between the Kit andPDGFRa genes. We have determined the precise location of the breakpoint of the Wshinversion and the endpoints of the W57deletion upstream of the Kittranscription start site and examined the effect of these mutations on Kit expression in mast cells and hematopoietic stem cells and lineage progenitors. Our results indicate that positive elements controlling Kit expression in mast cells mapping in between −23 and −154 kb from the transcription start site can be dissociated from negative elements controlling Kit misexpression during embryonic development in the vicinity of the PDGFRa gene. In addition, we have identified two clusters of hypersensitive sites in mast cells at −23 −28 kb and −147 −154 kb from the Kit gene transcription start site. Analysis of these hypersensitive sites in mutant mast cells indicates a role for HS4-6 in Kit expression in mast cells. These findings provide a molecular basis for the phenotype of these Kit expression mutations and they provide insight into the complex mechanisms governing the regulation ofKit expression.

Details

Language :
English
ISSN :
00064971 and 15280020
Volume :
94
Issue :
8
Database :
Supplemental Index
Journal :
Blood
Publication Type :
Periodical
Accession number :
ejs53055478
Full Text :
https://doi.org/10.1182/blood.V94.8.2658.420k23_2658_2666