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

Abstract

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-1s (L1s), are strongly methylated. These m6A-marked intronic L1s (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 L1s 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.

Active endogenous retroviral elements in human pluripotent stem cells play a role in regulating host gene expression

“…A few studies have shown that LTRs can enrich certain active histone modifications and transcription factors, and act as cis -regulatory elements to regulate host gene expression, such as serving as species-specific transcriptional insulators or providing transcription factor binding sites ( 14–16 ). During species evolution, all transposable elements accumulate mutations and gradually lose their transcription factor binding site motifs and thus reduce the ability of regulating host genes ( 17 , 18 ). In other words, the younger the evolutionary age is, the transposon would be closer to its full length and the less mutations are accumulated, and with a stronger the regulatory ability of transposable elements would be.…”

DNA-guided photoactivatable probe-based chemical proteomics reveals the reader protein of mRNA methylation

“…They belong to the nuclear RNA exosomes complex (NEXT) ( Lubas et al., 2015 ; Wu et al., 2019 ), which are responsible for eliminating redundant transcripts and maintaining the steady-state levels of diverse RNA species. Previous study showed that many classes of retro-transposable elements (RTE) RNAs, particularly intronic LINE1, are strongly m 6 A-methylated in mESCs, and 43% transcripts of retrotransposon element LINE1 are found to be targeted by the ZCCHC8 and RBM7 in NEXT ( Xiong et al., 2021 ). Thus we assume that m 6 A may act as a mark to be recognized by ZCCHC8 and RBM7 for the degradation of LINE1 RNAs.…”

RNA m6A Modification in Immunocytes and DNA Repair: The Biological Functions and Prospects in Clinical Application

“…Subsequent studies have confirmed that METTL14 arginine methylation is associated with the enhanced translation of DNA repair genes (Wang Z et al, 2021). Recent studies even clarified the correlation between DNA damage repair and m 6 A-modified retrotransposable element (RTE) RNAs, in which intronic Long Interspersed Element-1 (LINE-1) interacts with the hosting gene transcription, resulting in the downregulation of its expression (Xiong et al, 2021). KIAA1429 was also recently discovered to have close links with the modulation of response to cisplatin in germ cell tumor by interfering with DNA damage response (Miranda-Gonçalves et al, 2021).…”