Biology subjects

Abdulkarim, B.

Publications and source records attributed to Abdulkarim, B..

3 recordsLinked to original sources

bioRxiv2020

Noncanonical targeting contributes significantly to miRNA-mediated regulation.

Determining which genes are targeted by miRNAs is crucial to elucidate their contributions to diverse biological processes in health and disease. Most miRNA target prediction tools rely on the identification of complementary regions between transcripts and miRNAs. Whereas important for target recognition, the presence of complementary sites is not sufficient to identify transcripts targeted by miRNAs. Here, we describe an unbiased statistical genomics approach that explores genetically driven changes in gene expression between human individuals. Using this approach, we identified transcripts that respond to physiological changes in miRNA levels. We found that a much smaller fraction of mRNAs expressed in lymphoblastoid cell lines (LCLs) than what is predicted by other tools is targeted by miRNAs. We estimate that each miRNA has a relatively small number of targets. The transcripts we predict to be miRNA targets are enriched in AGO-binding and previously validated miRNAs target interactions, supporting the reliability of our predictions. Consistent with previous analysis, these targets are also enriched among dosage sensitive and highly controlled genes. Almost a third of genes we predict to be miRNA targets lack sequence complementarity to the miRNA seed region (noncanonical targets). These noncanonical targets have higher complementary with the miRNA 3' end. The impact of miRNAs on the levels of their canonical or noncanonical targets is identical supporting the relevance of this poorly explored mechanism of targeting.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2020

Translation is required for miRNA-dependent decay of endogenous transcripts.

Posttranscriptional repression by microRNA (miRNA) occurs through transcript destabilization or translation inhibition. Whereas RNA degradation explains most miRNA-dependent repression, transcript decay occurs co-translationally, raising questions regarding the requirement of target translation to miRNA-dependent transcript destabilization. To assess the contribution of translation to miRNA-mediated RNA destabilization, we decoupled these two molecular processes by dissecting the impact of miRNA loss of function on cytosolic long noncoding RNAs (lncRNAs). We show, that despite interacting with miRNA loaded RNA-induced silencing complex (miRISC), the steady state abundance and degradation rates of these endogenously expressed non-translated transcripts are minimally impacted by miRNA loss. To validate the requirement of translation for miRNA-dependent decay, we fused a miRISC bound lncRNA, whose levels are unaffected by miRNAs, to the 3end of a protein-coding gene reporter and show that this results in its miRNA-dependent transcript destabilization. Furthermore, analysis of the few lncRNAs whose levels are regulated by miRNAs revealed these tend to associate with translating ribosomes and are likely misannotated micropeptides, further substantiating the necessity of target translation for miRNA-dependent transcript decay. Our analyses reveal the strict requirement of translation for miRNA-dependent transcript destabilization and demonstrate that the levels of coding and noncoding transcripts are differently affected by miRNAs.

genomics↗

bioRxiv2019

The contribution of lincRNAs at the interface between cell cycle regulation and cell state maintenance

Cell cycle progression requires dynamic and tightly-regulated transitions between well-defined cell cycle stages. These transitions are controlled by the interplay of established cell cycle regulators. Changes in the activity of these regulators are thought to underpin differences in cell cycle kinetics between distinct cell types. Here, we investigate whether cell type-specific long intergenic noncoding RNAs (lincRNAs) contribute to embryonic stem cell adaptations, which have been shown to be essential for the maintenance of embryonic stem cell state. We used single cell RNA-sequencing data of mouse embryonic stem cells (mESC) staged as G1, S, or G2/M to identify genes differentially expressed between these phases. We found differentially expressed lincRNAs to be enriched amongst cell cycle regulated genes. These cell cycle associated lincRNAs (CC-lincRNAs) are co-expressed with protein-coding genes with established roles in cell cycle progression. Interestingly, 70% of CC-lincRNAs are differentially expressed between G1 and S, suggesting they may contribute to the maintenance of the short G1 phase that characterizes the embryonic stem cell cycle. Consistent with this hypothesis, the promoters of CC-lincRNAs are enriched in pluripotency transcription factor binding sites, and their transcripts are frequently co-regulated with genes involved in the maintenance of pluripotency. We tested the impact of 2 CC-lincRNA candidates and show that modulation of their expression is associated with impaired cell cycle progression, further underlining the contribution of mESC-specific lincRNAs to cell cycle modulation in these cells.

genomics↗