Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology ICGEB, 34149 Trieste, Italy.
Cell Host Microbe. 2013 Jun 12;13(6):665-77. doi: 10.1016/j.chom.2013.05.006.
Nuclear bodies (NBs), characterized by the presence of the promyelocytic leukemia (PML) protein, are important components of the nuclear architecture, contributing to genetic and epigenetic control of gene expression. In investigating the mechanisms mediating HIV-1 latency, we determined that silenced but transcriptionally competent HIV-1 proviruses reside in close proximity to PML NBs and that this association inhibits HIV-1 gene expression. PML binds to the latent HIV-1 promoter, which coincides with transcriptionally inactive facultative heterochromatic marks, notably H3K9me2, at the viral genome. PML degradation and NB disruption result in strong activation of viral transcription as well as release of G9a, the major methyltransferase responsible for H3K9me2, and loss of facultative heterochromatin marks from the proviral DNA. Additionally, HIV-1 transcriptional activation requires proviral displacement from PML NBs by active nuclear actin polymerization. Thus, nuclear topology and active gene movement mediate HIV-1 transcriptional regulation and have implications for controlling HIV-1 latency and eradication.
核体（NBs）的特征是存在早幼粒细胞白血病（PML）蛋白，是核架构的重要组成部分，有助于遗传和表观遗传控制基因表达。在研究介导 HIV-1 潜伏的机制时，我们确定沉默但转录功能完备的 HIV-1 前病毒与 PML NBs 紧密接近，这种关联抑制了 HIV-1 基因表达。PML 与潜伏的 HIV-1 启动子结合，该启动子与转录不活跃的兼性异染色质标记，特别是病毒基因组上的 H3K9me2 重合。PML 的降解和 NB 的破坏导致病毒转录的强烈激活，以及主要负责 H3K9me2 的甲基转移酶 G9a 的释放，以及前病毒 DNA 上的兼性异染色质标记的丢失。此外，HIV-1 转录激活需要前病毒通过活性核肌动蛋白聚合从 PML NBs 上置换。因此，核拓扑结构和活性基因运动介导 HIV-1 转录调控，并对控制 HIV-1 潜伏和消除具有重要意义。
