The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity

Liu, Jiadong; Gao, Mingwei; He, Jiangping; Wu, Kaixin; Lin, Siyuan; Jin, Lingmei; Chen, Yaping; Li, He; Shi, Junjie; Wang, Xiwei; Chao, Lei; Lin, Yingying; Zhao, Yuli; Zhang, Xiaofei; Zhang, Man; Luo, Guan‐Zheng; Wu, Guangming; Pei, Duanqing; Wang, Jie; Bao, Xichen; Chen, Jiekai

doi:10.1038/s41586-021-03313-9

Cited by 214 publications

(252 citation statements)

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“…4 However, the most abundant mRNA modification, N 6 -adenosine methylation (m 6 A), has only recently been detected in RNA from retrotransposons. [5][6][7] First, a CRISPR screen performed in mouse embryonic stem cells and designed to identify regulators of retroviral-like retrotransposons, the IAP elements, discovered that the m 6 A writers METTL3 and METTL14 are key regulators of retrotransposon RNA stability. Notably, they exert opposing effects on different retrotransposon families: while m 6 A destabilizes intracisternal A particle RNA, it appears to stabilize L1 RNA.…”

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confidence: 99%

“…Notably, they exert opposing effects on different retrotransposon families: while m 6 A destabilizes intracisternal A particle RNA, it appears to stabilize L1 RNA. 5 Furthermore, m 6 A RNA modifications may regulate the formation or maintenance of retrotransposon-associated heterochromatin, at least at specific retrotransposon loci, possibly through chromatinassociated RNA. 6,8 In a new study published in Cell Research, Xiong et al 9 explore m 6 A RNA modifications in nascent transcripts of human cells using a newly developed method, termed MINT-seq, that provides much higher intronic coverage than previous studies.…”

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confidence: 99%

“…5 Furthermore, m 6 A RNA modifications may regulate the formation or maintenance of retrotransposon-associated heterochromatin, at least at specific retrotransposon loci, possibly through chromatinassociated RNA. 6,8 In a new study published in Cell Research, Xiong et al 9 explore m 6 A RNA modifications in nascent transcripts of human cells using a newly developed method, termed MINT-seq, that provides much higher intronic coverage than previous studies. They observe that RNA segments derived from L1 elements and embedded in introns in the sense orientation relative to genes are particularly enriched in m 6 A modifications.…”

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confidence: 99%

“…6,8 In a new study published in Cell Research, Xiong et al 9 explore m 6 A RNA modifications in nascent transcripts of human cells using a newly developed method, termed MINT-seq, that provides much higher intronic coverage than previous studies. They observe that RNA segments derived from L1 elements and embedded in introns in the sense orientation relative to genes are particularly enriched in m 6 A modifications. Such m 6 A-rich domains, called MILs for m 6 A-rich intronic L1s, are characterized by decreased transcriptional elongation downstream of L1 (Fig.…”

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confidence: 99%

“…They observe that RNA segments derived from L1 elements and embedded in introns in the sense orientation relative to genes are particularly enriched in m 6 A modifications. Such m 6 A-rich domains, called MILs for m 6 A-rich intronic L1s, are characterized by decreased transcriptional elongation downstream of L1 (Fig. 1a).…”

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Nascent RNA m6A modification at the heart of the gene–retrotransposon conflict

Billon

Cristofari

2021

Cell Res

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Retrotransposons are highly abundant mobile genetic elements in mammalian genomes and can interfere with many genomic processes, particularly the transcription of genes. A study by Xiong et al. reveals that segments of nascent RNAs containing retrotransposons are enriched in N 6 -methyladenosine and act as transcriptional roadblocks for elongating RNA polymerase II, but that cellular proteins capable of binding to these RNAs, SAFB/SAFB2, can mitigate this effect.Long interspersed element 1 (L1) retrotransposons are transposable elements capable of propagating within genomes by a copy-and-paste mechanism through an RNA intermediate and a reverse transcription step. They are present in many eukaryotic lineages, but have been, and still are, particularly active in mammals, acting as potent endogenous mutagens. They are strongly silenced by several layers of transcriptional and posttranscriptional mechanisms, both in the nucleus and in the

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Nascent RNA m6A modification at the heart of the gene–retrotransposon conflict

Billon

Cristofari

2021

Cell Res

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An update on post‐transcriptional regulation of retrotransposons

Warkocki

2022

FEBS Letters

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Retrotransposons, including LINE-1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy-paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double-strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi-layered regulatory processes to prevent the dangerous effects of their expression. In recent years, significant progress was made in revealing how retrotransposon biology intertwines with general posttranscriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post-transcriptional factors in the biology of retrotransposons, focusing on LINE-1. I emphasize general RNA metabolisms such as methylation of adenine (m 6 A), RNA 3 0 -end polyadenylation and uridylation, RNA decay and translation regulation. I discuss the effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles.

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