Autonomous transposons tune their sequences to ensure somatic suppression [SAFKD_1H4_DHX9_FLASH]
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. Overall design: FLASH libraries of p-SR (mAb 1H4) and DHX9 in HEK293 cells that were either treated with control siRNA or siRNAs against SAFB1, SAFB2 and SLTM.