Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Mol Cell. 2018 Dec 20;72(6):970-984.e7. doi: 10.1016/j.molcel.2018.10.011. Epub 2018 Nov 15.
Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNAs are generally short lived, length restricted, and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly, depletion of the ubiquitous Pol-II-associated transcription elongation factor SPT6 promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes, which correlates with increased lncRNA transcription. SPT6 knockdown also impairs the recruitment of the Integrator complex to chromatin, which results in a transcriptional termination defect for lncRNA genes. This leads to the formation of extended, polyadenylated lncRNAs that are both chromatin restricted and form increased levels of RNA:DNA hybrid (R-loops) that are associated with DNA damage. Additionally, these deregulated lncRNAs overlap with DNA replication origins leading to localized DNA replication stress and a cellular senescence phenotype. Overall, our results underline the importance of restricting lncRNA expression.
哺乳动物基因组中缺乏蛋白质编码功能的大片段仍被转录为长非编码 RNA。虽然这些 lncRNA 通常寿命短、长度受限且非多聚腺苷酸化，但它们的表达如何与蛋白质编码基因区分开来仍然是个谜。令人惊讶的是，普遍存在的 Pol-II 相关转录延伸因子 SPT6 的耗竭会促进 H3K36me3 组蛋白标记从活跃的蛋白质编码基因重新分配到 lncRNA 基因，这与 lncRNA 转录的增加相关。SPT6 敲低还会损害整合酶复合物向染色质的募集，导致 lncRNA 基因的转录终止缺陷。这导致形成了延伸的、多聚腺苷酸化的 lncRNA，这些 lncRNA 既受到染色质的限制，又形成了更多的 RNA:DNA 杂交 (R-环)，这些杂交与 DNA 损伤有关。此外，这些失调的 lncRNA 与 DNA 复制起点重叠，导致局部 DNA 复制应激和细胞衰老表型。总的来说，我们的结果强调了限制 lncRNA 表达的重要性。
