Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence
收藏干细胞与再生医学数据中心2022-02-20 更新2024-03-06 收录
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RNA polymerase II (Pol II) generates interspersed protein-coding and long noncoding (lnc) transcripts across the mammalian genome. We recently established that lncRNAs are transcribed by different Pol II CTD isoforms correlating with reduced RNA processing efficiency and increased RNA turnover. How protein-coding and lncRNA transcription units are distinguished during gene expression remains unclear. We now show that H3K36me3 chromatin is a predominant epigenetic mark for active protein-coding but not lncRNA genes. Surprisingly depletion of the Pol II associated transcription elongation factor SPT6, causes redistribution of H3K36me3 histone marks to lncRNA genes which correlates with increased lncRNA transcription. SPT6 knockdown also reduces recruitment of Integrator complex to chromatin resulting in a transcription termination defect for lncRNA genes. Notably these extended lncRNAs are both chromatin-restricted and form increased levels of RNA:DNA hybrid (R-loops) with associated DNA damage. This results in a cellular senescence phenotype and underlies the importance of restricting lncRNA expression.
提供机构：
University of Oxford
创建时间：
2022-02-20
