SMYD5 methylation of rpL40 links ribosomal output to gastric cancer.

Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites.

loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion.

Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental disorder (NDD) with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by inactivating mutations in or tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs ("rapalogs") for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations.

Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.

Background: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins.

Translatome analysis of Tuberous Sclerosis Complex-1 patient-derived neural progenitor cells reveal rapamycin-dependent and independent alterations.

Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in or genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD). The hamartin-tuberin (TSC1-TSC2) protein complex inactivates mechanistic target of rapamycin complex 1 (mTORC1) signaling, leading to increased protein synthesis via inactivation of translational repressor eIF4E-binding proteins (4E-BPs). In -null neural progenitor cells (NPCs), we previously reported early ND phenotypic changes, including increased proliferation/altered neurite outgrowth, which were unaffected by mTORC1-inhibitor rapamycin.

Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR.

The integrated stress response (ISR) plays a pivotal role in adaptation of translation machinery to cellular stress. Here, we demonstrate an ISR-independent osmoadaptation mechanism involving reprogramming of translation via coordinated but independent actions of mTOR and plasma membrane amino acid transporter SNAT2. This biphasic response entails reduced global protein synthesis and mTOR signaling followed by translation of SNAT2.

flexiMAP: a regression-based method for discovering differential alternative polyadenylation events in standard RNA-seq data.

Motivation: We present flexible Modeling of Alternative PolyAdenylation (flexiMAP), a new beta-regression-based method implemented in R, for discovering differential alternative polyadenylation events in standard RNA-seq data.

Results: We show, using both simulated and real data, that flexiMAP exhibits a good balance between specificity and sensitivity and compares favourably to existing methods, especially at low fold changes. In addition, the tests on simulated data reveal some hitherto unrecognized caveats of existing methods.

Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression.

Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation.

Untranslated Parts of Genes Interpreted: Making Heads or Tails of High-Throughput Transcriptomic Data via Computational Methods: Computational methods to discover and quantify isoforms with alternative untranslated regions.

In this review we highlight the importance of defining the untranslated parts of transcripts, and present a number of computational approaches for the discovery and quantification of alternative transcription start and poly-adenylation events in high-throughput transcriptomic data. The fate of eukaryotic transcripts is closely linked to their untranslated regions, which are determined by the position at which transcription starts and ends at a genomic locus. Although the extent of alternative transcription starts and alternative poly-adenylation sites has been revealed by sequencing methods focused on the ends of transcripts, the application of these methods is not yet widely adopted by the community.

Dysregulation of Alternative Poly-adenylation as a Potential Player in Autism Spectrum Disorder.

We present here the hypothesis that alternative poly-adenylation (APA) is dysregulated in the brains of individuals affected by Autism Spectrum Disorder (ASD), due to disruptions in the calcium signaling networks. APA, the process of selecting different poly-adenylation sites on the same gene, yielding transcripts with different-length 3' untranslated regions (UTRs), has been documented in different tissues, stages of development and pathologic conditions. Differential use of poly-adenylation sites has been shown to regulate the function, stability, localization and translation efficiency of target RNAs.

iGEMS: an integrated model for identification of alternative exon usage events.

DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations.

Multiple sources of bias confound functional enrichment analysis of global -omics data.

Serious and underappreciated sources of bias mean that extreme caution should be applied when using or interpreting functional enrichment analysis to validate findings from global RNA- or protein-expression analyses.