Transcriptome protection by the expanded family of hnRNPs

Abstract

The family of heterogeneous ribonucleoproteins (hnRNPs) have multiple functions in RNA metabolism. In recent years, several hnRNPs have also been shown to be essential for the maintenance of transcriptome integrity, by preventing intronic cryptic splicing signals from mis-splicing of many endogeneous pre-mRNA transcripts. Here we discuss the possibility for a general role of this family of proteins and their expansion in transcriptome protection.

Keywords: Hnrnps; cryptic splicing; introns; transcriptome integrity.

Figure 1.

Correlation of the total number of hnRNP or hnRNP-like proteins with the total length of genes (a), genome length (b) and the number of genes (c) in 269 species. The coefficients R² show that the differentially expanded number of hnRNPs correlates better with the evolving total lengths of genes and genome sizes than the total number of genes among different species. The total number of hnRNPs of these Ensembl genomes/species were obtained from the NCBI Gene database by searching for the term ‘hnRNP’ in the ‘gene name’, ‘other designations’ or the ‘conserved domain’ sections of the records. The data are from 76 fungal, 120 metazoa, 30 plant and 43 protist species. The species with the highest number of hnRNPs in this search is the chimpanzee (44), followed by humans (42); the species with at least 1 hnRNP found are mostly fungi or protists. The presented trendline in each panel has the highest R² among fitting curves using linear, exponential, logarithmic or power functions. In C, the gene numbers also positively correlate with the hnRNP numbers overall but in a more scattered way than in A and B. Even after the outlier species with total numbers of genes >50K were excluded, the R² was 0.5587, still much lower than those in A and B. Search within only the ‘Domain name’ of NCBI Genes has resulted in similar correlations. A separate, manual verification of such hnRNPs of 21 species obtained a similar result as well, particularly with the correlation with gene lengths mainly in the total lengths of introns.

Figure 2.

Transcriptome protection by different hnRNPs. hnRNP L binds to CA/AC-rich motifs to inhibit cryptic exon/splice sites requiring PRR domain. hnRNPA1/A2B1 (Das and Xie, unpublished observation), PTBP1/P2, hnRNP C and TDP43 bind to GGG, CU-, U- and UG-rich motifs, respectively, to prevent cryptic exon (red box) inclusion. PRR: Proline-rich region, RRM: RNA recognition motif. SR: arginine/serine-rich proteins that are generally splicing activators and interact with the exons. The ovals represent the different domains/regions of the hnRNP proteins. For simplicity, the pre-mRNA and hnRNP are ‘stretched’ linearly. The splicing pathways in the presence (+) or absence (-) of hnRNPs are indicated with lines above or below the transcript. There are likely more hnRNPs (……) to be identified to protect the endogenous pre-mRNA transcripts of the transcriptome.