86 research outputs found
CLIP analysis identifies coregulated <i>in vivo</i> targets of novel master regulators of translation in the human heart.
No full text(A) Described functions by Van Nostrand et al. for the set of TE-RBPs. Functions related to translation (translation regulation and ribosome basic translation) are highlighted with dark red boxes. (B-C) Scatter plots representing the correlation of heart (B) and primary cardiac fibroblasts (C) translational efficiencies between UCHL5 and U2AF2 and two shared targets, KPNA4 and MYL6. UCHL5 and U2AF2 have marked opposite effects on their shared targets, indicative of a competitive effect replicated in two independent datasets. Scores and level of significance of the two Spearman’s correlations are displayed. (TIF)</p
Differential affinity of multifunctional RBPs for 5’ UTR structures often drives opposite quantitative TE effects.
No full text(A) Box and violin plots with 5’ UTR lengths for positively and negatively correlated TE targets corresponding to DDX3X, EFTUD2, and PRPF8. (B) Box and violin plots with length normalized MFE scores for positively and negatively correlated TE targets. We subsampled sets of 50 genes per group and RBP, so each of the groups had a similar distribution of 5’ UTR lengths. For comparison, non-correlating target genes were included in the panel figure. (C) Enriched GO terms in the sets of positive and negative correlating targets for DDX3X, EFTUD2, and PRPF8. For each RBP, the 5 most significant GO terms are displayed. (TIF)</p
CLIP analysis identifies coregulated <i>in vivo</i> targets of novel master regulators of translation in the human heart.
No full text(A) Heatmap displaying the hierarchically clustered correlations between the cardiac expression levels of the 37 TE-RBPs (as determined by normalized Ribo-seq expression) and the cardiac TE of 6,153 correlating target genes. Each of the significantly correlating target genes was previously found to be bound by at least one of these 37 TE-RBPs based on CLIP experiments (see Methods). The clustering separates two groups with opposite effects on TE, whose targets are enriched for mRNA metabolism (padj = 6.17 x 10−54) and endoplasmic reticulum (padj = 1.82 x 10−7) GO terms, respectively. (B) Dendrogram with hierarchically clustered TE-RBPs based on pairwise RBP-RBP overlaps. Shared target genes of all paired RBPs were included for clustering. Bottom heatmaps with translational efficiency correlations of selected RBP clusters and shared significant targets. These plots illustrate distinct cooperative and competitive RBP-target regulation modes. Pie charts illustrate the fraction of targets that remain significant after correcting for RBP collinearity per cluster. STRING protein-protein interaction networks [40] from selected RBP clusters reveal functional association of coregulated RBPs. Colours in edges and nodes indicate the sources of STRING evidence and known RBP functions. (C) Heatmap with hierarchically clustered Spearman’s Rho correlation scores of RBM20 and the translational efficiency of the predicted target genes. Significant correlating targets (n = 163, padj ≤ 0.05) and targets involved in muscle process (GO: 0003012) are highlighted in orange and light blue colours respectively. A list of sarcomere gene targets positively correlating with RBM20 is displayed. Selected bottom histograms illustrate the significance of RBM20 with correlating TE targets and the absence of significance with correlating mRNA targets. (D) Scatter plots representing the correlation between RBM20 expression (as measured by normalized Ribo-seq counts; x-axis) and the translational efficiency (TE; y-axis) of two sarcomere genes: TNNI3K and TTN. Score and level of significance of the two Spearman’s correlations are displayed. (E) Left: Scatter plot showing the correlation between normalized RBM20 expression levels (as measured by Ribo-seq) and the percent spliced in (PSI) of TTN exon 156. Right: Box plot comparing average TTN I-Band isoform-specific TEs, showing a marked difference between TTN isoform N2B (ENST00000460472), displaying a significantly higher TE than TTN isoform N2BA (ENST00000591111) (Wilcoxon rank sum test, p-value = 0.034).</p
RData object containing correlation matrices, global result- and effect-size tables for all mRNA-RBPs and TE-RBPs as well as a table with MFE values for all target transcripts for each TE-RBP.
No full textTo access this file, download R and load the RData object with the R function load: load(RData). (ZIP)</p
Multifunctional RBPs regulate translation of distinct sets of target genes.
No full text(A) Heatmap with Glass’ △ scores quantifying the effect size of the witness effects for mRNA and TE correlations. Both effect sizes are significant for a highlighted set of 21 multifunctional RBPs. For this set of RBPs, individual Venn Diagrams representing the overlap in the total number of mRNA and TE targets are displayed. (B) Bar plot quantifying the magnitude of mRNA and TE effect size (Glass’ △ scores) for multifunctional RBPs. RBP effect sizes are largely independent of the mode of regulation. (C) Selected histograms and dot plots illustrating the significance of RBP-target correlations and the enrichment of GO terms for the targets bound by 4 multifunctional RBPs: DDX3X, G3BP1, PUM1, and UCHL5. For each RBP, the 12 most significant parental GO terms are displayed. For three of the RBPs, mRNA and TE targets exhibit different enrichment of significant GO terms. (D) Box plots with transcript, 5’ UTR, CDS, and 3’ UTR sequence lengths in nucleotides for mRNA and TE targets corresponding to the four selected multifunctional RBPs in (C). A total of 9 multifunctional RBPs bind targets with significantly different CDS lengths (Wilcoxon rank sum test). See also S3 Fig.</p
Evolution and implications of de novo genes in humans
No full textGenes and translated open reading frames (ORFs) that emerged de novo from previously non-coding sequences provide species with opportunities for adaptation. When aberrantly activated, some human-specific de novo genes and ORFs have disease-promoting properties—for instance, driving tumour growth. Thousands of putative de novo coding sequences have been described in humans, but we still do not know what fraction of those ORFs has readily acquired a function. Here, we discuss the challenges and controversies surrounding the detection, mechanisms of origin, annotation, validation and characterization of de novo genes and ORFs. Through manual curation of literature and databases, we provide a thorough table with most de novo genes reported for humans to date. We re-evaluate each locus by tracing the enabling mutations and list proposed disease associations, protein characteristics and supporting evidence for translation and protein detection. This work will support future explorations of de novo genes and ORFs in humans
RNA-binding protein abundance predicts target translational regulation.
No full text(A) Schematic of the RBP-target correlation approach. Using the quantified Ribo-seq and RNA-seq data from 80 hearts, pairwise RBP versus target mRNA abundance or translational efficiency correlations were calculated. A heatmap with hierarchically clustered translational efficiency Spearman’s Rho correlations of RBPs and translated mRNAs in the human heart are shown. Six clusters of coregulated RBPs are highlighted (See also S1 Table). (B) Heatmap with Glass’ △ scores that quantify the effect size of the witnessed significance of associations between RBPs and target gene mRNA abundance and TE. Only significant RBPs are shown: 37 TE-RBPs (orange) and 58 mRNA-RBPs (green). For three selected RBPs (one per category), histograms illustrate the significance of the calculated associations. (C) Dot plot displaying the fraction of translational efficiency RBP-target correlations that can be replicated in an independent set of primary cardiac fibroblasts [30]. For each RBP, the significance of the replication was evaluated by comparing the replicated fraction between observed and randomized sets and it is represented as a brown (significant) or red (non-significant) dot. The size of the dots indicates the strength of significance (-log10 (padj)) and grey dots correspond to the fraction of replicated correlations in randomized sets. Error bars indicate mean values with standard deviation (SD).</p
RData object containing DESeq2 normalized poly(A) RNA-seq and Ribo-seq count matrices together, TE matrix (Ribo-seq/RNA-seq) and PSI count matrix.
No full textTo access this file, download R and load the RData object with the R function load: load(RData). (ZIP)</p
Multifunctional RBPs’ localization.
No full textTable with all 21 multifunctional RBPs and their cellular localization (0: absent; 1: present). (XLSX)</p
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