RNA m6A modification orchestrates a LINE-1-host interaction that facilitates retrotransposition and contributes to long gene vulnerability

• 作者: Feng Xiong Ruoyu Wang Joo-Hyung Lee Shenglan Li Shin-Fu Chen Zian Liao Lana Al Hasani Phuoc T.Nguyen Xiaoyu Zhu Joanna Krakowiak Dung-Fang Lee Leng Han Kuang-Lei Tsai Ying Liu Wenbo Li
• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2021,（8）
• 所属期刊栏目: ARTICLES
• 页码范围: 861-885
• 页数: 25页
• 语种: 英文

摘要

The molecular basis underlying the interaction between retrotransposable elements(RTEs)and the human genome remains poorly understood.Here,we profiled N6-methyladenosine(m6A)deposition on nascent RNAs in human cells by developing a new method MINT-Seq,which revealed that many classes of RTE RNAs,particularly intronic LINE-1 s(L1s),are strongly methylated.These(m)6A-marked(i)ntronic(L)1s(MILs)are evolutionarily young,sense-oriented to hosting genes,and are bound by a dozen RNA binding proteins(RBPs)that are putative novel readers of m6A-modified RNAs,including a nuclear matrix protein SAFB.Notably,m6A positively controls the expression of both autonomous L1 s and co-transcribed L1 relics,promoting L1 retrotransposition.We showed that MILs preferentially reside in long genes with critical roles in DNA damage repair and sometimes in L1 suppression per se,where they act as transcriptional"roadblocks"to impede the hosting gene expression,revealing a novel host-weakening strategy by the L1s.In counteraction,the host uses the SAFB reader complex to bind m6A-L1s to reduce their levels,and to safeguard hosting gene transcription.Remarkably,our analysis identified thousands of MILs in multiple human fetal tissues,enlisting them as a novel category of cell-type-specific regulatory elements that often compromise transcription of long genes and confer their vulnerability in neurodevelopmental disorders.We propose that this m6A-orchestrated L1-host interaction plays widespread roles in gene regulation,genome integrity,human development and diseases.