Biology subjects

Abou Elela, S.

Publications and source records attributed to Abou Elela, S..

10 recordsLinked to original sources

bioRxiv2026

A Ribosomal RNA modification regulates translation of PI3K/AKT activators in high-grade serous ovarian carcinoma

PI3K/AKT signalling is a key driver of ovarian cancer progression and an important therapeutic target. Its deregulation is usually explained by genetic changes and altered signalling at the cell surface. Here, we identify an additional layer of pathway control, in which a change in the level of a cancer-associated ribosomal RNA modification alters the translation of proteins that regulate PI3K/AKT activity. SNORA81 is a high-grade serous ovarian carcinoma-associated H/ACA small nucleolar RNA that directs pseudouridylation of 28S ribosomal RNA at position U4636. Integration of tumour transcriptomes with independent SNORA81-depletion datasets identified 22 SNORA81-linked transcripts with reversed disease-associated expression, 19 of them linked to PI3K/AKT signalling. SNORA81 depletion reduced AKT phosphorylation, impaired cell growth, migration, and altered cell-cycle distribution. Molecularly, polysome profiling following SNORA81 depletion identified 524 mRNAs with altered ribosome association, 485 of which changed independently of RNA abundance and included 29 PI3K/AKT regulators. SNORA81 depletion reduced ribosome association of ITGB4, RASGRP2, IGF1 and FGF18 transcripts, and reduced ITGB4 and RASGRP2 protein abundance. IRAK1 and SPC24 acted as downstream RNA-response genes contributing to selected SNORA81-associated phenotypes. ITGB4 expression partially restored cell growth and restored downstream RNA responses after SNORA81 depletion. These findings identify rRNA modification as a translational regulator of PI3K/AKT signalling in ovarian cancer.

cancer biology↗

bioRxiv2026

A ribosomal pseudouridine drives an oncogenic translation program

Dynamic ribosome heterogeneity has emerged as a potential layer of translational regulation, but whether variation in ribosomal RNA (rRNA) modification stoichiometry can selectively control the translation of mRNAs with shared encoded features remains unclear. Here we show that SNORA81-guided pseudouridylation at U4636 controls a selective translational program in ovarian cancer cells. U4636 is partially pseudouridylated and lies within 28S rRNA near eL31 and the peptide exit tunnel. Depletion of SNORA81 reduces pseudouridylation at U4636 without broadly perturbing rRNA processing or bulk translation. Instead, it remodels codon-specific and nascent-peptide-associated pausing and the polysome association of SNORA81-dependent translationally altered mRNAs. These mRNAs display characteristic GC content and amino-acid composition, are enriched in cancer-related functions and show corresponding changes in protein levels. Our findings support a model in which a change in the abundance of a single snoRNA propagates from rRNA-modification stoichiometry through ribosome dynamics and selective mRNA translation to protein output and cancer cell proliferation. We term this multilevel amplification cascade the "sno-balling" effect.

cancer biology↗

bioRxiv2026

A starvation-remodeled pre-mRNA structure controls U1 recruitment and nutrient-stress adaptation in yeast

Recognition of 5' splice sites by the U1 small nuclear ribonucleoprotein commits pre-mRNAs to splicing, yet splice-site complementarity alone cannot predict productive U1 engagement. Whether dynamic pre-mRNA structure regulates this early spliceosome assembly step remains unclear. Here, we identify a 5'UTR-intron base-pairing interaction positioned near the 5' splice site that acts as an inducible structural gate for U1 engagement. In budding yeast, this element is enriched among introns required for adaptation to nutrient depletion, and in vivo DMS-MaPseq shows that starvation remodels its structure. Structure-guided disruption of pairing impairs adaptation, whereas compensatory mutations restoring pairing without restoring sequence rescue the phenotype, establishing RNA fold as the critical determinant. U1 association decreases when the gate is disrupted and recovers when pairing is restored, and increased Nam8 levels can compensate for gate disruption by stabilizing U1 engagement under stress. Thus, dynamic pre-mRNA folding gates U1 recognition, revealing how transcript architecture converts physiological state into selective splice-site choice.

molecular biology↗

bioRxiv2026

Nanopore Direct RNA Sequencing Enables Reproducible, Site-Resolved Pseudouridine Quantification in Human Ribosomal RNA

Pseudouridine is the most abundant post-transcriptional modification in human ribosomal RNA, with over 110 annotated sites and variable stoichiometry across biological contexts. Existing quantification methods are low-throughput or constrained to predefined panels. We benchmarked nanopore direct RNA sequencing using the Dorado v5.1 model against mass spectrometry-validated sites in human liver tissue, induced pluripotent stem cells, and HeLa cells. Nanopore sequencing detected 95 of 117 validated sites and accurately quantified stoichiometry at 85% of sites with high reproducibility. Low GC-content environments were the primary source of failure. These results establish nanopore sequencing as a scalable tool for epitranscriptomic pseudouridine profiling.

biochemistry↗

bioRxiv2026

snoFlake: A network model for snoRNA-RBP complexes reveals SNORD22 as a U5 snRNP-associated splicing regulator

Small nucleolar RNAs (snoRNAs) are canonically viewed as stable components of ribonucleoprotein complexes dedicated to RNA modification. Here, we developed snoFlake, a snoRNA-centric interaction network integrating physical and functional associations between box C/D snoRNAs and RNA-binding proteins (RBPs), challenging this narrow view. Using snoFlake, we systematically identified snoRNAs predicted to form noncanonical complexes with diverse RBPs, extending their roles into post-transcriptional regulation. We found 23 high-confidence network motifs enriched for RNA-processing functions, including a top-ranked module linking SNORD22 to U5 snRNP components PRPF8 and EFTUD2. SNORD22 co-binds with these spliceosomal RBPs at splice sites showing reduced U5 snRNP occupancy, suggesting a role in reinforcing spliceosomal engagement at suboptimal exons. Consistently, SNORD22 depletion promotes exclusion of weak cassette exons, altering transcript isoform composition and predicted coding output. Beyond SNORD22, snoFlake reveals snoRNAs with similar network profiles, providing a resource for uncovering previously uncharacterized snoRNA-RBP complexes and expanding the functional snoRNome.

bioinformatics↗

bioRxiv2022

Altered tRNA processing is linked to a distinct and unusual La protein in Tetrahymena thermophila

Nascent pre-tRNAs are transcribed by RNA polymerase III and immediately bound by La proteins on the UUU-3OH sequence, using a tandem arrangement of the La motif and an adjacent RNA recognition motif-1 (RRM1), resulting in protection from 3-exonucleases and promotion of pre-tRNA folding. The Tetrahymena thermophila protein Mlp1 has been classified as a genuine La protein, despite the predicted absence of the RRM1. We found that Mlp1 functions as a La protein through binding of pre-tRNAs and affecting processing in Tetrahymena thermophila and when expressed in fission yeast. However, unlike in other examined eukaryotes, depletion of Mlp1 results in 3-trailer stabilization. We also observed that 3-trailers in Tetrahymena thermophila are uniquely short relative to other examined eukaryotes, and that 5-leaders have evolved to disfavour pre-tRNA leader/trailer pairing. Our data indicate that this variant Mlp1 architecture is linked to an altered, novel mechanism of tRNA processing in Tetrahymena thermophila.

molecular biology↗

bioRxiv2021

The snoGloBe interaction predictor enables a broader study of box C/D snoRNA functions and mechanisms

Box C/D small nucleolar RNAs (snoRNAs) are a conserved class of RNA known for their role in guiding ribosomal RNA 2-O-ribose methylation. Recently, C/D snoRNAs were also implicated in regulating the expression of non-ribosomal genes through different modes of binding. Large scale RNA-RNA interaction datasets detect many snoRNAs binding messenger RNA, but are limited by specific experimental conditions. To enable a more comprehensive study of C/D snoRNA interactions, we created snoGloBe, a human C/D snoRNA interaction predictor based on a gradient boosting classifier. SnoGloBe considers the target type, position and sequence of the interactions, enabling it to outperform existing predictors. Interestingly, for specific snoRNAs, snoGloBe identifies strong enrichment of interactions near gene expression regulatory elements including splice sites. Abundance and splicing of predicted targets were altered upon the knockdown of their associated snoRNA. Strikingly, the predicted snoRNA interactions often overlap with the binding sites of functionally related RNA binding proteins, reinforcing their role in gene expression regulation. SnoGloBe is also an excellent tool for discovering viral RNA targets, as shown by its capacity to identify snoRNAs targeting the heavily methylated SARS-CoV-2 RNA. Overall, snoGloBe is capable of identifying experimentally validated binding sites and predicting novel sites with shared regulatory function.

bioinformatics↗

bioRxiv2021

High-grade Ovarian Cancer Associated H/ACA snoRNAs Promote Cancer Cell Proliferation and Survival

Small nucleolar RNAs (snoRNAs) are an omnipresent class of non-coding RNAs involved in the modification and processing of ribosomal RNA (rRNA). As snoRNAs are required for ribosome production, the increase of which is a hallmark of cancer development, their expression would be expected to increase in proliferating cancer cells. However, the nature and extent of snoRNAs contribution to the biology of cancer cells remain largely unexplored. In this study, we examined the abundance patterns of snoRNA in high-grade serous ovarian carcinomas (HGSC) and serous borderline tumours (SBT) and identified a subset of snoRNA associated with increased invasiveness. This subgroup of snoRNA accurately discriminates between SBT and HGSC underlining their potential as biomarkers of tumour aggressiveness. Remarkably, knockdown of HGSC-associated H/ACA snoRNAs, but not their host genes, inhibits cell proliferation and induces apoptosis of model ovarian cancer cell lines. Wound healing and cell migration assays confirmed the requirement of these HGSC-associated snoRNA for cell invasion and increased tumour aggressiveness. Together our data indicate that H/ACA snoRNAs promote tumour aggressiveness through the induction of cell proliferation and resistance to apoptosis.

cancer biology↗

bioRxiv2021

Dynamics and modulation of the human snoRNome

BackgroundSmall nucleolar RNAs (snoRNAs) are mid-size non-coding RNAs required for ribosomal RNA modification, implying a ubiquitous tissue distribution linked to ribosome synthesis. However, increasing numbers of studies identify extra-ribosomal roles of snoRNAs in modulating gene expression, suggesting more complex snoRNA abundance patterns. Therefore, there is a great need for mapping the snoRNome in different human tissues as the blueprint for snoRNA functions. ResultsWe used a low structure bias RNA-Seq approach to accurately quantify snoRNAs and compare them to the entire transcriptome in seven healthy human tissues (breast, ovary, prostate, testis, skeletal muscle, liver and brain). We identified 475 expressed snoRNAs categorized in two abundance classes that differ significantly in their function, conservation level and correlation with their host gene: 390 snoRNAs are uniformly expressed and 85 are enriched in the brain or reproductive tissues. Most tissue-enriched snoRNAs are embedded in lncRNAs and display strong correlation of abundance with them, whereas uniformly expressed snoRNAs are mostly embedded in protein-coding host genes and are mainly non- or anticorrelated with them. 59% of the non-correlated or anticorrelated protein-coding host gene/snoRNA pairs feature dual-initiation promoters, as opposed to only 16% of the correlated non-coding host gene/snoRNA pairs. ConclusionsOur results demonstrate that snoRNAs are not a single homogeneous group of housekeeping genes but include highly regulated tissue-enriched RNAs. Indeed, our work indicates that the architecture of snoRNA host genes varies to uncouple the host and snoRNA expressions in order to meet the different snoRNA abundance levels and functional needs of human tissues.

genomics↗

bioRxiv2018

CoCo: RNA-seq Read Assignment Correction for Nested Genes and Multimapped Reads

MotivationNext generation sequencing techniques revolutionized the study of RNA expression by permitting whole transcriptome analysis. However, sequencing reads generated from nested and multi-copy genes are often either misassigned or discarded, which greatly reduces both quantification accuracy and gene coverage.\n\nResultsHere we present CoCo, a read assignment pipeline that takes into account the multitude of overlapping and repetitive genes in the transcriptome of higher eukaryotes. CoCo uses a modified annotation file that highlights nested genes and proportionally distributes multimapped reads between repeated sequences. CoCo salvages over 15% of discarded aligned RNA-seq reads and significantly changes the abundance estimates for both coding and non-coding RNA as validated by PCR and bed-graph comparisons.\n\nAvailabilityThe CoCo software is an open source package written in Python and available from http://gitlabscottgroup.med.usherbrooke.ca/scott-group/coco.\n\nContactmichelle.scott@usherbrooke.ca

bioinformatics↗