Heteromeric RNP Assembly at LINEs Controls Lineage-Specific RNA Processing

• Published in: Cell Vol. 174; no. 5; pp. 1067 - 1081.e17
• Main Authors: Attig, Jan, Agostini, Federico, Gooding, Clare, Chakrabarti, Anob M., Singh, Aarti, Haberman, Nejc, Zagalak, Julian A., Emmett, Warren, Smith, Christopher W.J., Luscombe, Nicholas M., Ule, Jernej
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-08-2018; Cell Press
• Subjects: alternative polyadenylation; Alternative Splicing; Animals; Binding Sites; CLIP; cryptic exons; evolution; exonogenesis; Exons; HeLa Cells; Heterogeneous-Nuclear Ribonucleoproteins - chemistry; Humans; Introns; LINE repeats; Long Interspersed Nucleotide Elements; MATR3; Mice; multivalency; Mutation; Nuclear Matrix-Associated Proteins - chemistry; Nucleotide Motifs; Phylogeny; Polyadenylation; Polypyrimidine Tract-Binding Protein - chemistry; Protein Binding; Protein Interaction Mapping; PTBP1; RNA - chemistry; RNA Splicing; RNA-Binding Proteins - chemistry; splicing; PTBP1; cryptic exons; LINE repeats; MATR3; splicing; evolution; multivalency; exonogenesis; alternative polyadenylation; CLIP
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.07.001

Long mammalian introns make it challenging for the RNA processing machinery to identify exons accurately. We find that LINE-derived sequences (LINEs) contribute to this selection by recruiting dozens of RNA-binding proteins (RBPs) to introns. This includes MATR3, which promotes binding of PTBP1 to multivalent binding sites within LINEs. Both RBPs repress splicing and 3′ end processing within and around LINEs. Notably, repressive RBPs preferentially bind to evolutionarily young LINEs, which are located far from exons. These RBPs insulate the LINEs and the surrounding intronic regions from RNA processing. Upon evolutionary divergence, changes in RNA motifs within LINEs lead to gradual loss of their insulation. Hence, older LINEs are located closer to exons, are a common source of tissue-specific exons, and increasingly bind to RBPs that enhance RNA processing. Thus, LINEs are hubs for the assembly of repressive RBPs and also contribute to the evolution of new, lineage-specific transcripts in mammals.
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•Multivalent binding sites in young LINEs mainly recruit repressive RBPs•PTBP1 and MATR3 co-bind and repress RNA processing within and around young LINEs•1-kb exclusion zone of LINEs from vicinity of exons reflects their repressive effects•Sequence-driven RBP remodeling on old LINEs drives evolution of tissue-specific exons
LINE elements recruit RNA-binding proteins to mammalian introns, influencing splicing and playing a key role in the evolution of tissue-specific exons.