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Mouse Huntington's disease homolog mRNA levels: variation and allele effects.

机译:小鼠亨廷顿舞蹈病同源mRNA水平:变异和等位基因效应。

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Huntington's disease homolog (Hdh) mRNA levels in mice with different Hdh alleles were measured. Brain Hdh mRNA levels varied up to threefold in genetically identical wild-type mice, indicating nongenetic factors influence Hdh expression. Striatal Hdh mRNA levels from an allele with a repeat expanded to 150 CAGs were diminished compared with wild-type and showed variation that might contribute to phenotypic variability in the Hdh(CAG)150 knock-in mouse model. To determine whether Hdh mRNA levels are tightly regulated, we assessed these levels in mice heterozygous for a deletion of the Hdh promoter. The loss of one allele reduced Hdh mRNA levels in most tissues, suggesting mechanisms to maintain Hdh mRNA levels are not in effect and should not impede therapies designed to destroy mutant huntingtin mRNA. Finally, we found a correlation between tissue mRNA levels and the susceptibility of the Hdh locus to Cre-mediated deletion. The two tissues with the highest levels of Hdh mRNA, testes and brain, were the only tissues susceptible to Cre-mediated recombination between loxP sites at Hdh locus. In contrast, the same Cre-expressing line caused recombination in every tissue for loxP sites at another genomic location. The pattern of Cre susceptibility at Hdh suggests a correlation between chromatin accessibility and high levels of Hdh expression in testes and brain.
机译:测量具有不同Hdh等位基因的小鼠中的亨廷顿舞蹈病同源基因(Hdh)mRNA水平。在基因上相同的野生型小鼠中,大脑Hdh mRNA水平变化高达三倍,表明非遗传因素影响Hdh表达。与野生型相比,等位基因重复扩增至150个CAG的纹状体Hdh mRNA水平降低,显示出可能有助于Hdh(CAG)150敲入小鼠模型表型变异的变异。为了确定Hdh mRNA水平是否受到严格调节,我们评估了杂合子中Hdh启动子缺失的这些水平。一个等位基因的缺失会降低大多数组织中的Hdh mRNA水平,这表明维持Hdh mRNA水平的机制并不起作用,并且不应阻碍旨在破坏突变型huntingtin mRNA的疗法。最后,我们发现组织mRNA水平与Hdh基因座对Cre介导的缺失的敏感性之间存在相关性。 Hdh mRNA水平最高的两个组织,即睾丸和大脑,是唯一对Cre介导的Hdh基因座loxP位点之间的重组介导重组的组织。相反,相同的Cre表达系导致每个组织中另一个基因组位置的loxP位点重组。 Hdh的Cre易感性模式表明,染色质可及性与睾丸和大脑中Hdh高表达之间存在相关性。

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