The nascent m6A methylome in human cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE137752 | GEO | 2021/05/14
REPOSITORIES: GEO
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Project description:Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-mRNA synthesis, intronic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product as they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns (Huff et al. 2016), and functional (Cosby et al. 2021) or non-functional chimeric transcripts (Clayton et al. 2020). The rarity of these events impliesy the existence of a resilient splicing code that is able to suppress TE-exonization without compromising host pre-mRNA processing. Here we show that SAFB proteins play a unique dual role in defence against TEs by preventing retrotransposition of L1 elements as well as their exonization when they land into genes by coating their adenosine-rich RNA. The suppressive activity of SAFB extends to neuro-, muscle- and testis-specific giant protein-coding cassette exons of ANK3, MAP4 and CLIP1, nested genes as well as Tigger DNA transposons, which are all enriched with adenosine/purine-rich sequences that act as splicing-enhancers in SAFB depleted cells. In mice and flies, SAFB additionally suppresses LTR/ERV elements, which are active in mice and flies, but no longer in humans. Splicing events suppressed by SAFB in somatic cells are activated in the testis, coinciding with low SAFB expression in post-meiotic spermatids. Reminiscent of the division of labour between innate and adaptive immune systems that fight external pathogens, our results uncover SAFB proteins as an RNA-based, pattern-guided, non-adaptive defence system against TEs in the soma, complementing the RNA-based, adaptive Piwi-piRNA pathway of the germline.
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Project description:Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-mRNA synthesis, intronic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product as they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns (Huff et al. 2016), and functional (Cosby et al. 2021) or non-functional chimeric transcripts (Clayton et al. 2020). The rarity of these events impliesy the existence of a resilient splicing code that is able to suppress TE-exonization without compromising host pre-mRNA processing. Here we show that SAFB proteins play a unique dual role in defence against TEs by preventing retrotransposition of L1 elements as well as their exonization when they land into genes by coating their adenosine-rich RNA. The suppressive activity of SAFB extends to neuro-, muscle- and testis-specific giant protein-coding cassette exons of ANK3, MAP4 and CLIP1, nested genes as well as Tigger DNA transposons, which are all enriched with adenosine/purine-rich sequences that act as splicing-enhancers in SAFB depleted cells. In mice and flies, SAFB additionally suppresses LTR/ERV elements, which are active in mice and flies, but no longer in humans. Splicing events suppressed by SAFB in somatic cells are activated in the testis, coinciding with low SAFB expression in post-meiotic spermatids. Reminiscent of the division of labour between innate and adaptive immune systems that fight external pathogens, our results uncover SAFB proteins as an RNA-based, pattern-guided, non-adaptive defence system against TEs in the soma, complementing the RNA-based, adaptive Piwi-piRNA pathway of the germline.
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Project description:Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-mRNA synthesis, intronic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product as they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns (Huff et al. 2016), and functional (Cosby et al. 2021) or non-functional chimeric transcripts (Clayton et al. 2020). The rarity of these events impliesy the existence of a resilient splicing code that is able to suppress TE-exonization without compromising host pre-mRNA processing. Here we show that SAFB proteins play a unique dual role in defence against TEs by preventing retrotransposition of L1 elements as well as their exonization when they land into genes by coating their adenosine-rich RNA. The suppressive activity of SAFB extends to neuro-, muscle- and testis-specific giant protein-coding cassette exons of ANK3, MAP4 and CLIP1, nested genes as well as Tigger DNA transposons, which are all enriched with adenosine/purine-rich sequences that act as splicing-enhancers in SAFB depleted cells. In mice and flies, SAFB additionally suppresses LTR/ERV elements, which are active in mice and flies, but no longer in humans. Splicing events suppressed by SAFB in somatic cells are activated in the testis, coinciding with low SAFB expression in post-meiotic spermatids. Reminiscent of the division of labour between innate and adaptive immune systems that fight external pathogens, our results uncover SAFB proteins as an RNA-based, pattern-guided, non-adaptive defence system against TEs in the soma, complementing the RNA-based, adaptive Piwi-piRNA pathway of the germline.
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Project description:<p>Insertions of the human-specific subfamily of LINE-1 (L1) retrotransposon are highly polymorphic across individuals and can critically influence the human transcriptome. We hypothesized that L1 insertions could represent genetic variants determining important human phenotypic traits, and performed an integrated analysis of L1 elements and single nucleotide polymorphisms (SNPs) in several human populations. We found that a large fraction of L1s were in high linkage disequilibrium (LD) with their surrounding genomic regions and that they were well-tagged by SNPs. However, L1 variants were only partially captured by SNPs on standard SNP arrays, so that their potential phenotypic impact would be frequently missed by SNP array-based genome-wide association studies. We next identified potential phenotypic effects of L1s by looking for signatures of natural selection linked to L1 insertions; significant extended haplotype homozygosity (EHH) was detected around several L1 insertions. This suggests that some of these L1 insertions may have been the target of recent positive selection.</p>
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Project description:Transposable elements (TEs) are a major constituent of human genes, occupying approximately half of the intronic space. During pre-mRNA synthesis, intronŁic TEs are transcribed along with their host genes but rarely contribute to the final mRNA product as they are spliced out together with the intron and rapidly degraded. Paradoxically, TEs are an abundant source of RNA-processing signals through which they can create new introns (Huff et al. 2016), and functional (Cosby et al. 2021) or non-functional chimeric transcripts (Clayton et al. 2020). The rarity of these events impliesy the existence of a resilient splicing code that is able to suppress TE-exonization without compromising host pre-mRNA processing. Here we show that SAFB proteins play a unique dual role in defence against TEs by preventing retrotransposition of L1 elements as well as their exonization when they land into genes by coating their adenosine-rich RNA. The suppressive activity of SAFB extends to neuro-, muscle- and testis-specific giant protein-coding cassette exons of ANK3, MAP4 and CLIP1, nested genes as well as Tigger DNA transposons, which are all enriched with adenosine/purine-rich sequences that act as splicing-enhancers in SAFB depleted cells. In mice and flies, SAFB additionally suppresses LTR/ERV elements, which are active in mice and flies, but no longer in humans. Splicing events suppressed by SAFB in somatic cells are activated in the testis, coinciding with low SAFB expression in post-meiotic spermatids. Reminiscent of the division of labour between innate and adaptive immune systems that fight external pathogens, our results uncover SAFB proteins as an RNA-based, pattern-guided, non-adaptive defence system against TEs in the soma, complementing the RNA-based, adaptive Piwi-piRNA pathway of the germline.
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