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Transcription-dependent silencing of inducible convergent transgenes in transgenic mice

机译：转基因小鼠中诱导收敛性转基因的转录依赖性沉默。

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Background Silencing of transgenes in mice is a common phenomenon typically associated with short multi-copy transgenes. We have investigated the regulation of the highly inducible human granulocyte-macrophage colony-stimulating-factor gene (Csf2) in transgenic mice. Results In the absence of any previous history of transcriptional activation, this transgene was expressed in T lineage cells at the correct inducible level in all lines of mice tested. In contrast, the transgene was silenced in a specific subset of lines in T cells that had encountered a previous episode of activation. Transgene silencing appeared to be both transcription-dependent and mediated by epigenetic mechanisms. Silencing was accompanied by loss of DNase I hypersensitive sites and inability to recruit RNA polymerase II upon stimulation. This pattern of silencing was reflected by increased methylation and decreased acetylation of histone H3 K9 in the transgene. We found that silenced lines were specifically associated with a single pair of tail-to-tail inverted repeated copies of the transgene embedded within a multi-copy array. Conclusions Our study suggests that epigenetic transgene silencing can result from convergent transcription of inverted repeats which can lead to silencing of an entire multi-copy transgene array. This mechanism may account for a significant proportion of the reported cases of transgene inactivation in mice.
机译：背景转基因小鼠的沉默是常见的现象，通常与短多拷贝转基因有关。我们已经研究了转基因小鼠中高度诱导的人类粒细胞巨噬细胞集落刺激因子基因（Csf2）的调节。结果在没有任何先前转录激活历史的情况下，该转基因在所有测试的小鼠品系中以正确的诱导水平在T谱系细胞中表达。相反，转基因在遇到先前激活事件的T细胞中特定的细胞系子集中沉默。转基因沉默似乎既依赖转录，又受表观遗传机制介导。沉默伴随着DNase I超敏位点的丧失和刺激后不能募集RNA聚合酶II。这种沉默模式通过转基因中组蛋白H3 K9的甲基化增强和乙酰化降低而得以体现。我们发现沉默的谱系与嵌入多拷贝阵列中的转基因的单对尾对尾反向重复重复序列特别相关。结论我们的研究表明，表观遗传转基因沉默可能源于反向重复序列的收敛转录，从而导致整个多拷贝转基因阵列的沉默。该机制可能占所报道的小鼠转基因失活病例的很大一部分。

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