A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion

Abstract Background Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. Results We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. Conclusions We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.

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Trans control of cardiac mRNA translation in a protein length-dependent fashion

10.1101/2020.06.05.133298 ◽

2020 ◽

Author(s):

Franziska Witte ◽

Jorge Ruiz-Orera ◽

Camilla Ciolli Mattioli ◽

Susanne Blachut ◽

Eleonora Adami ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Translation Initiation ◽

Phenotypic Variability ◽

Mrna Translation ◽

Translational Efficiency ◽

Ribosome Assembly ◽

List Type ◽

Master Regulator ◽

Protein Length ◽

The Impact

ABSTRACTLittle is known about the impact of naturally occurring genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate how genetic influences on mRNA translational efficiency are associated with complex disease phenotypes using a panel of rat recombinant inbred lines. We identify a locus for cardiac hypertrophy that is associated with a translatome-wide and protein length-dependent shift in translational efficiency. This master regulator primarily affects the translation of very short and very long protein-coding sequences, altering the physiological stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus points to altered ribosome assembly, characterized by accumulation of polysome half-mers, changed ribosomal configurations and misregulation of the small nucleolar RNA SNORA48. We postulate that this locus enhances a pre-existing negative correlation between protein length and translation initiation in diseased hearts. Our work shows that a single genomic locus can trigger a complex, translation-driven molecular mechanism that contributes to phenotypic variability between individuals.Graphical AbstractHighlightsGenetic variability impacts protein synthesis rates in a rat model for cardiac hypertrophyA trans locus affects stoichiometric translation rates of cardiac sarcomeric proteinsThis master regulator locus induces a global, protein length-dependent shift in translationDysregulated ribosome assembly induces half-mer formation and affects translation initiation rate

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Estrogen receptor alpha controls gene expression via translational offsetting

10.1101/507574 ◽

2018 ◽

Author(s):

Julie Lorent ◽

Richard J. Rebello ◽

Vincent van Hoef ◽

Mitchell G. Lawrence ◽

Krzysztof J. Szkop ◽

...

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Alpha ◽

Mrna Translation ◽

Translational Efficiency ◽

Cancer Cell Proliferation ◽

Altered Expression ◽

Receptor Alpha ◽

Protein Levels ◽

Transcriptional Output ◽

The Impact

AbstractEstrogen 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. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNA and protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translational efficiency including structured 5’UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modification enzymes, whereas altered expression of U34-modification enzymes disrupts ERα dependent translational offsetting. Altogether, we unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs, and highlight that translational offsetting may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.

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Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver

10.1101/432823 ◽

2018 ◽

Cited By ~ 1

Author(s):

Minal Çalışkan ◽

Elisabetta Manduchi ◽

H. Shanker Rao ◽

Julian A Segert ◽

Marcia Holsbach Beltrame ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Histone Modification ◽

Human Liver ◽

Complex Disease ◽

Regulation Of Gene Expression ◽

Regulatory Elements ◽

Chromatin Interaction ◽

Genome Wide ◽

The Impact

ABSTRACTDeciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

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Short structural variants as informative genetic markers for ALS disease risk and progression

BMC Medicine ◽

10.1186/s12916-021-02206-y ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Frances Theunissen ◽

Loren L. Flynn ◽

Ryan S. Anderton ◽

P. Anthony Akkari

Keyword(s):

Clinical Trials ◽

Genetic Markers ◽

Complex Disease ◽

Disease Risk ◽

Phenotypic Variability ◽

Disease Onset ◽

Structural Variations ◽

Genomic Regions ◽

Als Patients ◽

The Impact

AbstractThere is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1, SCAF4, and STMN2, we hope to improve the outcomes of future ALS clinical trials.

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The Pseudomonas aeruginosa Transcriptional Landscape Is Shaped by Environmental Heterogeneity and Genetic Variation

mBio ◽

10.1128/mbio.00749-15 ◽

2015 ◽

Vol 6 (4) ◽

Cited By ~ 47

Author(s):

Andreas Dötsch ◽

Monika Schniederjans ◽

Ariane Khaledi ◽

Klaus Hornischer ◽

Sebastian Schulz ◽

...

Keyword(s):

Gene Expression ◽

Pseudomonas Aeruginosa ◽

Genetic Variation ◽

Expression Profiles ◽

Phenotypic Variability ◽

Gene Expression Profiles ◽

Environmental Cues ◽

Content Type ◽

The Impact ◽

Transcriptional Landscape

ABSTRACTPhenotypic variability among bacteria depends on gene expression in response to different environments, and it also reflects differences in genomic structure. In this study, we analyzed transcriptome sequencing (RNA-seq) profiles of 151Pseudomonas aeruginosaclinical isolates under standard laboratory conditions and of oneP. aeruginosatype strain under 14 different environmental conditions. Our approach allowed dissection of the impact of the genetic background versus environmental cues onP. aeruginosagene expression profiles and revealed that phenotypic variation was larger in response to changing environments than between genomically different isolates. We demonstrate that mutations within the global regulator LasR affect more than one trait (pleiotropy) and that the interaction between mutations (epistasis) shapes theP. aeruginosaphenotypic plasticity landscape. Because of pleiotropic and epistatic effects, average genotype and phenotype measures appeared to be uncorrelated inP. aeruginosa.IMPORTANCEThis work links experimental data of unprecedented complexity with evolution theory and delineates the transcriptional landscape of the opportunistic pathogenPseudomonas aeruginosa. We found that gene expression profiles are most strongly influenced by environmental cues, while at the same time the transcriptional profiles were also shaped considerably by genetic variation within global regulators. The comprehensive set of transcriptomic and genomic data of more than 150 clinicalP. aeruginosaisolates will be made publically accessible to all researchers via a dedicated web interface. BothPseudomonasspecialists interested in expression and regulation of specific genes and researchers from other fields with more global interest in the phenotypic and genotypic variation of this important model species can access all information on various levels of detail.

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Upregulation of 5′-terminal oligopyrimidine mRNA translation upon loss of the ARF tumor suppressor

Scientific Reports ◽

10.1038/s41598-020-79379-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kyle A. Cottrell ◽

Ryan C. Chiou ◽

Jason D. Weber

Keyword(s):

Protein Synthesis ◽

Tumor Cells ◽

Ribosomal Proteins ◽

Human Cancer ◽

Mrna Translation ◽

Ribosome Profiling ◽

Translational Efficiency ◽

Gene Encoding ◽

Terminal Oligopyrimidine ◽

Ribosome Export

AbstractTumor cells require nominal increases in protein synthesis in order to maintain high proliferation rates. As such, tumor cells must acquire enhanced ribosome production. How the numerous mutations in tumor cells ultimately achieve this aberrant production is largely unknown. The gene encoding ARF is the most commonly deleted gene in human cancer. ARF plays a significant role in regulating ribosomal RNA synthesis and processing, ribosome export into the cytoplasm, and global protein synthesis. Utilizing ribosome profiling, we show that ARF is a major suppressor of 5′-terminal oligopyrimidine mRNA translation. Genes with increased translational efficiency following loss of ARF include many ribosomal proteins and translation factors. Knockout of p53 largely phenocopies ARF loss, with increased protein synthesis and expression of 5′-TOP encoded proteins. The 5′-TOP regulators eIF4G1 and LARP1 are upregulated in Arf- and p53-null cells.

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Gut-Ex-Vivo system as a model to study gluten response in celiac disease

Cell Death Discovery ◽

10.1038/s41420-021-00430-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Mara Gagliardi ◽

Nausicaa Clemente ◽

Romina Monzani ◽

Luca Fusaro ◽

Eleonora Ferrari ◽

...

Keyword(s):

Celiac Disease ◽

Intestinal Epithelium ◽

Complex Disease ◽

Ex Vivo ◽

Dynamic Condition ◽

Model Systems ◽

In Vivo Models ◽

Effective Manner ◽

Junction Protein ◽

The Impact

AbstractCeliac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.

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Quantitative Trait Loci for the Monoamine-Related Traits Heart Rate and Headless Behavior inDrosophila melanogaster

Genetics ◽

10.1093/genetics/157.1.283 ◽

2001 ◽

Vol 157 (1) ◽

pp. 283-294 ◽

Cited By ~ 2

Author(s):

Kristie Ashton ◽

Ana Patricia Wagoner ◽

Roland Carrillo ◽

Greg Gibson

Keyword(s):

Heart Rate ◽

Genetic Variation ◽

Recombinant Inbred Lines ◽

Model Organism ◽

Interval Mapping ◽

Activity Levels ◽

Environmental Variance ◽

Genome Wide ◽

A Genome ◽

Monoamine Receptors

AbstractDrosophila melanogaster appears to be well suited as a model organism for quantitative pharmacogenetic analysis. A genome-wide deficiency screen for haploinsufficient effects on prepupal heart rate identified nine regions of the genome that significantly reduce (five deficiencies) or increase (four deficiencies) heart rate across a range of genetic backgrounds. Candidate genes include several neurotransmitter receptor loci, particularly monoamine receptors, consistent with results of prior pharmacological manipulations of heart rate, as well as genes associated with paralytic phenotypes. Significant genetic variation is also shown to exist for a suite of four autonomic behaviors that are exhibited spontaneously upon decapitation, namely, grooming, grasping, righting, and quivering. Overall activity levels are increased by application of particular concentrations of the drugs octopamine and nicotine, but due to high environmental variance both within and among replicate vials, the significance of genetic variation among wild-type lines for response to the drugs is difficult to establish. An interval mapping design was also used to map two or three QTL for each behavioral trait in a set of recombinant inbred lines derived from the laboratory stocks Oregon-R and 2b.

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