The Wsh, W57, and Ph Kit expression mutations define tissue-specific control elements located between-23 and-154 kb upstream of Kit
The Wsh, W57, and Ph Kit expression mutations define tissue-specific control elements located between-23 and-154 kb upstream of Kit
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DOI：
10.1182/blood.v94.8.2658.420k23_2658_2666
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发表时间：
1999-10-15
期刊：
影响因子：
20.3
通讯作者：
Besmer, P
中科院分区：
文献类型：
--
作者：
Berrozpe, G;Timokhina, I;Besmer, P
Kit和PDGFRA受体酪氨酸激酶是在小鼠白斑(W)和斑块(Ph)基因座上编码的。W突变影响造血、黑素生成和配子发生，Ph突变影响黑素合成并导致纯合子早期死亡，而W-sh、W-57和Ph突变降低某些细胞类型(如肥大细胞)中Kit的表达，并增强其他细胞类型中的Kit表达。W-sh、W-57和Ph突变是由影响Kit和PDGFRA基因之间序列的缺失和倒置引起的。我们已经确定了W-sh倒置的断裂点和W-57缺失的终点在Kit转录起始点上游的准确位置，并检测了这些突变对肥大细胞、造血干细胞和谱系祖细胞Kit表达的影响。我们的结果表明，在PDGFRA基因附近，控制肥大细胞Kit表达的-23-154 kb之间的正性元件可以从控制Kit错误表达的负元件中分离出来，此外，我们还在肥大细胞中发现了两个位于Kit基因转录起始点-23-28kb和-147-154 kb的高敏感位点，对突变的肥大细胞中这些高敏感位点的分析表明HS4-6在肥大细胞Kit表达中起到了作用。这些发现为这些Kit表达突变的表型提供了分子基础，也为Kit表达调控的复杂机制提供了洞察力。(C)1999年由美国血液病学会主办。
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, W-57, and Ph mutations diminish Kit expression in certain cell types such as mast cells and enhance it in others. The W-sh, W-57, 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 W-57 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. (C) 1999 by The American Society of Hematology.