L1 retrotransposons exploit RNA m6A modification as an evolutionary driving force

Hwang, Sung-Yeon; Jung, Hyunchul; Mun, Seyoung; Lee, Sungwon; Park, Kiwon; Baek, Sungmin; Moon, Hyungseok C.; Kim, Hyewon; Kim, Baekgyu; Choi, Yu-Sung; Go, Young-Hyun; Tang, Wanxiangfu; Choi, Jong-Su; Choi, Jung Kyoon; Cha, Hyuk‐Jin; Park, Hye Yoon; Liang, Ping; Kim, V. Narry; Han, Kyudong; Ahn, Kwangseog

doi:10.1038/s41467-021-21197-1

Cited by 36 publications

(15 citation statements)

References 67 publications

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“…Both of these functions are important for RC-L1 to fulfill a complete life cycle, and both have been functionally connected to m 6 A on mRNAs. 96 , 105 , 125 – 128 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Both of these functions are important for RC-L1 to fulfill a complete life cycle, and both have been functionally connected to m 6 A on mRNAs. 96 , 105 , 125 – 128 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…In contrast, a 129-bp deletion in the 5’UTR (inclusive of the binding site) allowed a subset of L1PA3, L1PA2, and L1PA1 to escape ZNF93 suppression [ 25 ]. In addition, a single nucleotide change at position 333 created a functional m6A site, which first appeared in a subset of L1PA3 and then dominated in L1PA2 and L1PA1 [ 26 ]. Primate L1 5’UTRs also possess an antisense promoter, which drives the expression of a third open reading frame (ORF0) as well as chimeric fusion transcripts with upstream cellular genes [ 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

Subfamily-specific differential contribution of individual monomers and the tether sequence to mouse L1 promoter activity

Kong

Saha

et al. 2022

Mobile DNA

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Background The internal promoter in L1 5’UTR is critical for autonomous L1 transcription and initiating retrotransposition. Unlike the human genome, which features one contemporarily active subfamily, four subfamilies (A_I, Gf_I and Tf_I/II) have been amplifying in the mouse genome in the last one million years. Moreover, mouse L1 5’UTRs are organized into tandem repeats called monomers, which are separated from ORF1 by a tether domain. In this study, we aim to compare promoter activities across young mouse L1 subfamilies and investigate the contribution of individual monomers and the tether sequence. Results We observed an inverse relationship between subfamily age and the average number of monomers among evolutionarily young mouse L1 subfamilies. The youngest subgroup (A_I and Tf_I/II) on average carry 3–4 monomers in the 5’UTR. Using a single-vector dual-luciferase reporter assay, we compared promoter activities across six L1 subfamilies (A_I/II, Gf_I and Tf_I/II/III) and established their antisense promoter activities in a mouse embryonic fibroblast cell line and a mouse embryonal carcinoma cell line. Using consensus promoter sequences for three subfamilies (A_I, Gf_I and Tf_I), we dissected the differential roles of individual monomers and the tether domain in L1 promoter activity. We validated that, across multiple subfamilies, the second monomer consistently enhances the overall promoter activity. For individual promoter components, monomer 2 is consistently more active than the corresponding monomer 1 and/or the tether for each subfamily. Importantly, we revealed intricate interactions between monomer 2, monomer 1 and tether domains in a subfamily-specific manner. Furthermore, using three-monomer 5’UTRs, we established a complex nonlinear relationship between the length of the outmost monomer and the overall promoter activity. Conclusions The laboratory mouse is an important mammalian model system for human diseases as well as L1 biology. Our study extends previous findings and represents an important step toward a better understanding of the molecular mechanism controlling mouse L1 transcription as well as L1’s impact on development and disease.

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“…However, m6A-modified mRNA can recruit eIF3 in the absence of eIF4E and other components of the eIF4 complex, allowing the m6Amodified mRNAs to be translated in the presence of eIF3 and other priming factors (Orouji et al, 2020). Subsequent studies have also confirmed that m6A is required to recruit eIF3 to mRNA during protein translation (Hwang et al, 2021).…”

Section: M6a In Rna Nuclear Exportmentioning

confidence: 93%

The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review

Jing

Zhou

Ning

et al. 2021

Front. Cell Dev. Biol.

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Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, yet the molecular mechanisms underlying its onset and development have not yet been fully elucidated. Indeed, an in-depth understanding of the potential molecular mechanisms underlying HNSCC oncogenesis may aid the development of better treatment strategies. Recent epigenetic studies have revealed that the m6A RNA modification plays important roles in HNSCC. In this review, we summarize the role of m6A modification in various types of HNSCC, including thyroid, nasopharyngeal, hypopharyngeal squamous cell, and oral carcinoma. In addition, we discuss the regulatory roles of m6A in immune cells within the tumor microenvironment, as well as the potential molecular mechanisms. Finally, we review the development of potential targets for treating cancer based on the regulatory functions of m6A, with an aim to improving targeted therapies for HNSCC. Together, this review highlights the important roles that m6A modification plays in RNA synthesis, transport, and translation, and demonstrates that the regulation of m6A-related proteins can indirectly affect mRNA and ncRNA function, thus providing a novel strategy for reengineering intrinsic cell activity and developing simpler interventions to treat HNSCC.

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L1 retrotransposons exploit RNA m6A modification as an evolutionary driving force

Cited by 36 publications

References 67 publications

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

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

Subfamily-specific differential contribution of individual monomers and the tether sequence to mouse L1 promoter activity

The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review

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