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.
Highlights
Long Interspersed Elements (LINEs)-1 constitutes a major category of m6A-methylated RNAs in human cells We developed a new method to examine m6A landscape on nascent RNAs, which we refer to as m6A inscribed Nascent
A fraction of biotin-purified 4SU-marked nascent RNA was used for Transient Transcriptome sequencing (TT-Seq),[50] which served as the input for MINT-Seq (Supplementary information, Fig. S1a–c)
LINEs showed the highest numbers of MINT-Seq peaks (22.4% of all peaks), representing strong enrichment of m6A peaks (~4-fold higher than expected, Supplementary information, Fig. S2a)
Summary
Retrotransposable elements (RTEs), consisting of Long Interspersed Elements (LINEs), Short Interspersed Element (SINEs), and endogenous retroviruses (ERVs), make up nearly half of the mammalian genomes.[1,2] RTEs are major evolutionary parasites in the mammalian genomes that continuously develop new means to propagate, which on one hand threatens the stability of the host genome, but on the other can drive new genome evolution.[3,4,5,6,7,8,9] In humans, LINE-1 (or L1) is the most dominant RTEs in terms of the genome sizes they occupy (~17%–21%),[10,11] and is the only active category capable of autonomous retrotransposition.[6,12,13] To safeguard the genome integrity, the host employs a series of epigenetic strategies to suppress the transcription of L1 and other RTEs, e.g. DNA methylation[14] and histone methylation (e.g. H3K9me3).[15,16] Post-transcriptional mechanisms were involved in RTE suppression.[17,18] Recently, DNA damage repair (DDR) and replication related factors were identified as new suppressors of L1 activity.[11,19,20] as compared to these defense systems deployed by the hosts to suppress RTEs, it is less known as to how RTEs harness epigenetic mechanisms to benefit their own propagation, or how RTEs may exploit the vulnerability of the host genome to undermine its defense, and what the human genome uses to cope with these L1 actions
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