The W(sh), W(57), and Ph Kit expression mutations define tissue-specific control elements located between -23 and -154 kb upstream of Kit Journal Article

Authors: Berrozpe, G.; Timokhina, I.; Yukl, S.; Tajima, Y.; Ono, M.; Zelenetz, A. D.; Besmer, P.
Article Title: The W(sh), W(57), and Ph Kit expression mutations define tissue-specific control elements located between -23 and -154 kb upstream of Kit
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. The W(sh), W57, and Ph mutations diminish Kit expression in certain cell types such as mast cells and enhance it in others. The W(sh), W57, and Ph mutations arose from deletions and inversions affecting sequences in between the Kit and PDGFRa genes. We have determined the precise location of the breakpoint of the W(sh) inversion and the endpoints of the W57 deletion upstream of the Kit transcription 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 of Kit expression.
Keywords: gene mutation; gene deletion; sequence deletion; nonhuman; animal cell; mouse; animals; mice; bone marrow cells; stem cell factor; stem cell factor receptor; proto-oncogene proteins c-kit; receptor, platelet-derived growth factor alpha; transcription initiation; mice, mutant strains; gene locus; embryo development; platelet derived growth factor receptor; protein tyrosine kinase; mice, inbred c57bl; gene expression regulation; cloning, molecular; gene mapping; chromatin; organ specificity; hematopoietic stem cells; hematopoiesis; dna flanking region; hematopoietic stem cell; receptor protein-tyrosine kinases; dna mutational analysis; chromosome mapping; enzyme induction; mast cell; mast cells; chromosome inversion; inversion, chromosome; deoxyribonuclease i; priority journal; article
Journal Title: Blood
Volume: 94
Issue: 8
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 1999-10-15
Start Page: 2658
End Page: 2666
Language: English
PUBMED: 10515869
PROVIDER: scopus
Notes: Article -- Export Date: 16 August 2016 -- Source: Scopus