Murine leukemia virus (MLV) integrase (IN) lacking the C-terminal tail peptide (TP) loses its interaction with the host bromodomain and extraterminal (BET) proteins and displays decreased integration at promoter/enhancers and transcriptional start sites/CpG islands. MLV lacking the IN TP via an altered open reading frame was used to infect tumorigenesis mouse model (MYC/Runx2) animals to observe integration patterns and phenotypic effects, but viral passage resulted in the restoration of the IN TP through small deletions. Mice subsequently infected with an MLV IN lacking the TP coding sequence (TP-) showed an improved median survival by 15 days compared to wild type (WT) MLV infection. Recombination with polytropic endogenous retrovirus (ERV), Pmv20, was identified in seven mice displaying both fast and slow tumorigenesis, highlighting the strong selection within the mouse to maintain the full-length IN protein. Mapping the genomic locations of MLV in tumors from an infected mouse with no observed recombination with ERVs, TP-16, showed fewer integrations at TSS and CpG islands, compared to integrations observed in WT tumors. However, this mouse succumbed to the tumor in relatively rapid fashion (34 days). Analysis of the top copy number integrants in the TP-16 tumor revealed their proximity to known MLV common insertion site genes while maintaining the MLV IN TP- genotype. Furthermore, integration mapping in K562 cells revealed an insertion preference of MLV IN TP- within chromatin profile states associated with weakly transcribed heterochromatin with fewer integrations at histone marks associated with BET proteins (H3K4me1/2/3, and H3K27Ac). While MLV IN TP- showed a decreased overall rate of tumorigenesis compared to WT virus in the MYC/Runx2 model, MLV integration still occurred at regions associated with oncogenic driver genes independently from the influence of BET proteins, either stochastically or through trans-complementation by functional endogenous Gag-Pol protein.

中文翻译：

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破坏MLV整合酶：BET蛋白相互作用会使整合进入静态染色质并延迟，但并不能消除MYC / Runx2小鼠模型中的肿瘤激活。

缺少C末端尾巴肽（TP）的鼠白血病病毒（MLV）整合酶（IN）失去了与宿主溴结构域和末端（BET）蛋白的相互作用，并在启动子/增强子和转录起始位点/ CpG岛上显示出降低的整合。通过改变的开放阅读框缺少IN TP的MLV被用于感染肿瘤发生小鼠模型（MYC / Runx2）动物以观察整合模式和表型效应，但是病毒传代导致IN TP通过小的缺失得以恢复。随后被缺少TP编码序列（TP-）的MLV IN感染的小鼠与野生型（WT）MLV感染相比，其中位生存期提高了15天。在显示快速和慢速肿瘤发生的7只小鼠中鉴定出与多向性内源性逆转录病毒（ERV）Pmv20重组。强调了在小鼠中进行强烈选择以维持全长IN蛋白的作用。与未观察到与WT肿瘤中观察到的整合相比，对未观察到与ERV TP-16重组的被感染小鼠的肿瘤中MLV的基因组位置作图显示，在TSS和CpG岛上的整合较少。然而，该小鼠以相对快速的方式（34天）死于肿瘤。TP-16肿瘤中最高拷贝数整合子的分析显示，它们与已知的MLV常见插入位点基因接近，同时保持了MLV IN TP-基因型。此外，K562细胞中的整合图谱揭示了在与弱转录的异染色质相关的染色质分布状态下，MLV IN TP-的插入偏好，与BET蛋白（H3K4me1 / 2/3和H3K27Ac）相关的组蛋白标记处的整合较少。