A common class of transcripts with 5′-intron depletion, distinct early coding sequence features, and N¹-methyladenosine modification

Abstract

Introns are found in 5′ untranslated regions (5 ′ UTRs) for 35% of all human transcripts. These 5 ′ UTR introns are not randomly distributed: Genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5 ′ UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5′ UTR intron status, we developed a classifier that can predict 5′ UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5 ′ proximal-intron-minus-like-coding regions ("5IM" transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5 ′ cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the exon junction complex (EJC) at noncanonical 5 ′ proximal positions. Finally, N 1 -methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising ∼20% of human transcripts. This class is defined by depletion of 5 ′ proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N 1 -methyladenosines in the early coding region, and enrichment for noncanonical binding by the EJC.

Dynamic RNA Modifications in Gene Expression Regulation

“…This modification can be removed by ALKBH3, and is responsive to various types of cellular stress (Dominissini et al, 2016; Li et al, 2016). m 1 A may affect translation through facilitating non-canonical binding of the exon-exon junction complex at 5’ UTRs devoid of 5’ proximal introns (Cenik et al, 2017). …”

Sequence Determinants for Nuclear Retention and Cytoplasmic Export of mRNAs and lncRNAs

“…Similarly, N 5 -methylcytosine has also been reported to promote mRNA nuclear export by recruiting Aly to the transcript ( Yang et al, 2017 ). Although N 1 -methyladenosine has not been directly linked to export, this modification is enriched in the 5′ terminal exon of a particular class of mRNAs ( Cenik et al, 2017 ). These mRNAs have interesting 5′ terminal exons.…”

Epitranscriptomic influences on development and disease

“…m 1 A was also shown to affect translation; its presence at the first or second codon position, but not at the third codon, blocks translation in both Escherichia coli and wheat germ extract systems [ 65 ]. In addition, m 1 A is present in early coding regions of transcripts without 5′ UTR introns, which are associated with low translation efficiency and which facilitate noncanonical binding by the exon junction complex [ 66 ]. These studies point to a main role of m 1 A in translation and RNA–RNA interactions.…”