Nutrient Control of mRNA Translation

The emergence of genome-wide analyses to interrogate cellular DNA, RNA, and protein content has revolutionized the study of control networks that mediate cellular homeostasis. mRNA translation represents the last step of genetic flow and primarily defines the proteome. Translational regulation is thus critical for gene expression, in particular under nutrient excess or deficiency. Until recently, it was unclear how the global effects of translational control are orchestrated by nutrient signaling pathways. An emerging concept of translational reprogramming addresses how to maintain the expression of specific proteins during nutrient stress by translation of selective mRNAs. In this review, we describe recent advances in our understanding of translational control principles; nutrient-sensing mechanisms; and their dysregulation in human diseases such as diabetes, cancer, and aging. The mechanistic understanding of translational regulation in response to different nutrient conditions may help identify potential dietary and therapeutic targets to improve human health.

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Muscle specific translational control of Cand2 by mTORC1 regulates adverse cardiac remodeling

10.1101/2020.11.29.403196 ◽

2020 ◽

Author(s):

Agnieszka A. Gorska ◽

Clara Sandmann ◽

Eva Riechert ◽

Christoph Hofmann ◽

Ellen Malovrh ◽

...

Keyword(s):

Cardiac Remodeling ◽

Translational Control ◽

Translational Regulation ◽

Mrna Translation ◽

Specific Protein ◽

Expression Control ◽

Genome Wide ◽

Gene Expression Control ◽

Cell Type Specific ◽

Pathological Remodeling

AbstractThe mechanistic target of rapamycin (mTOR) is a key regulator of pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective, however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is largely unknown. A cardiomyocyte genome-wide sequencing approach was used to define mTOR-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified the muscle-specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we found that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type-specific targeting of mTOR might have therapeutic value for adverse pathological cardiac remodeling.

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Gcn2 eIF2α kinase mediates combinatorial translational regulation through nucleotide motifs and uORFs in target mRNAs

Nucleic Acids Research ◽

10.1093/nar/gkaa608 ◽

2020 ◽

Vol 48 (16) ◽

pp. 8977-8992 ◽

Cited By ~ 3

Author(s):

Yuji Chikashige ◽

Hiroaki Kato ◽

Mackenzie Thornton ◽

Whitney Pepper ◽

Madelyn Hilgers ◽

...

Keyword(s):

Translational Control ◽

Translational Regulation ◽

Mrna Translation ◽

Stress Signaling ◽

Dependent Manner ◽

Histone Acetyl Transferase ◽

Genome Wide ◽

Gene Transcripts ◽

Specific Mrnas ◽

Eif2α Kinase

Abstract The protein kinase Gcn2 is a central transducer of nutritional stress signaling important for stress adaptation by normal cells and the survival of cancer cells. In response to nutrient deprivation, Gcn2 phosphorylates eIF2α, thereby repressing general translation while enhancing translation of specific mRNAs with upstream ORFs (uORFs) situated in their 5′-leader regions. Here we performed genome-wide measurements of mRNA translation during histidine starvation in fission yeast Schizosaccharomyces pombe. Polysome analyses were combined with microarray measurements to identify gene transcripts whose translation was up-regulated in response to the stress in a Gcn2-dependent manner. We determined that translation is reprogrammed to enhance RNA metabolism and chromatin regulation and repress ribosome synthesis. Interestingly, translation of intron-containing mRNAs was up-regulated. The products of the regulated genes include additional eIF2α kinase Hri2 amplifying the stress signaling and Gcn5 histone acetyl transferase and transcription factors, together altering genome-wide transcription. Unique dipeptide-coding uORFs and nucleotide motifs, such as ‘5′-UGA(C/G)GG-3′, are found in 5′ leader regions of regulated genes and shown to be responsible for translational control.

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Comprehensive Genome-Wide Approaches to Activity-Dependent Translational Control in Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms21051592 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1592

Author(s):

Han Kyoung Choe ◽

Jun Cho

Keyword(s):

Gene Expression ◽

Translational Control ◽

Translational Regulation ◽

Molecular Mechanisms ◽

Regulation Of Gene Expression ◽

Autism Spectrum ◽

Specific Stimulus ◽

Genome Wide ◽

Activity Dependent ◽

The Brain

Activity-dependent regulation of gene expression is critical in experience-mediated changes in the brain. Although less appreciated than transcriptional control, translational control is a crucial regulatory step of activity-mediated gene expression in physiological and pathological conditions. In the first part of this review, we overview evidence demonstrating the importance of translational controls under the context of synaptic plasticity as well as learning and memory. Then, molecular mechanisms underlying the translational control, including post-translational modifications of translation factors, mTOR signaling pathway, and local translation, are explored. We also summarize how activity-dependent translational regulation is associated with neurodevelopmental and psychiatric disorders, such as autism spectrum disorder and depression. In the second part, we highlight how recent application of high-throughput sequencing techniques has added insight into genome-wide studies on translational regulation of neuronal genes. Sequencing-based strategies to identify molecular signatures of the active neuronal population responding to a specific stimulus are discussed. Overall, this review aims to highlight the implication of translational control for neuronal gene regulation and functions of the brain and to suggest prospects provided by the leading-edge techniques to study yet-unappreciated translational regulation in the nervous system.

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The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes

Reproduction ◽

10.1530/rep-08-0524 ◽

2009 ◽

Vol 137 (4) ◽

pp. 595-617 ◽

Cited By ~ 70

Author(s):

Matthew Brook ◽

Joel W S Smith ◽

Nicola K Gray

Keyword(s):

Gene Expression ◽

Germ Cells ◽

Translational Control ◽

Translational Regulation ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor

Gametogenesis is a highly complex process that requires the exquisite temporal, spatial and amplitudinal regulation of gene expression at multiple levels. Translational regulation is important in a wide variety of cell types but may be even more prevalent in germ cells, where periods of transcriptional quiescence necessitate the use of post-transcriptional mechanisms to effect changes in gene expression. Consistent with this, studies in multiple animal models have revealed an essential role for mRNA translation in the establishment and maintenance of reproductive competence. While studies in humans are less advanced, emerging evidence suggests that translational regulation plays a similarly important role in human germ cells and fertility. This review highlights specific mechanisms of translational regulation that play critical roles in oogenesis by activating subsets of mRNAs. These mRNAs are activated in a strictly determined temporal manner via elements located within their 3′UTR, which serve as binding sites fortrans-acting factors. While we concentrate on oogenesis, these regulatory events also play important roles during spermatogenesis. In particular, we focus on the deleted in azoospermia-like (DAZL) family of proteins, recently implicated in the translational control of specific mRNAs in germ cells; their relationship with the general translation initiation factor poly(A)-binding protein (PABP) and the process of cytoplasmic mRNA polyadenylation.

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A UV-Induced Mutation in Neurospora That Affects Translational Regulation in Response to Arginine

Genetics ◽

10.1093/genetics/142.1.117 ◽

1996 ◽

Vol 142 (1) ◽

pp. 117-127 ◽

Cited By ~ 3

Author(s):

Michael Freitag ◽

Nelima Dighde ◽

Matthew S Sachs

Keyword(s):

Translational Control ◽

Translational Regulation ◽

Fusion Gene ◽

Mrna Translation ◽

Small Subunit ◽

Upstream Open Reading Frame ◽

Control Mechanisms ◽

Carbamoyl Phosphate ◽

Altered Expression ◽

Reading Frame

The Neurospora crmsu arg-2 gene encodes the small subunit of arginine-specific carbamoyl phosphate synthetase. The levels of arg-2 mRNA and mRNA translation are negatively regulated by arginine. An upstream open reading frame (uORF) in the transcript’s 5′ region has been implicated in arginine-specific control. An arg-2-hph fusion gene encoding hygromycin phosphotransferase conferred arginine-regulated resistance to hygromycin when introduced into N. crassa. We used an arg-2-hph strain to select for UV-induced mutants that grew in the presence of hygromycin and arginine, and we isolated 46 mutants that had either of two phenotypes. One phenotype indicated altered expression of both arg-2-hph and urg-2 genes; the other, altered expression of urg-2-hph but not arg-2. One of the latter mutations, which was genetically closely linked to arg-2-hph, was recovered from the 5′ region of the arg-2-hph gene using PCR. Sequence analyses and transformation experiments revealed a mutation at uORF codon 12 (Asp to Asn) that abrogated negative regulation. Examination of the distribution of ribosomes on arg-2-hph transcripts showed that loss of regulation had a translational component, indicating the uORF sequence was important for Arg-specific translational control. Comparisons with other uORFS suggest common elements in translational control mechanisms.

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The Role of Translation Initiation Regulation in Haematopoiesis

Comparative and Functional Genomics ◽

10.1155/2012/576540 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Godfrey Grech ◽

Marieke von Lindern

Keyword(s):

Gene Expression ◽

Translation Initiation ◽

Translational Control ◽

Molecular Mechanisms ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Translation Control ◽

Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

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Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0022 ◽

2013 ◽

Vol 368 (1632) ◽

pp. 20130022 ◽

Cited By ~ 13

Author(s):

Noboru Jo Sakabe ◽

Marcelo A. Nobrega

Keyword(s):

Gene Expression ◽

Target Genes ◽

Expression Patterns ◽

Dna Interaction ◽

Regulatory Elements ◽

Specific Gene ◽

Genome Wide ◽

Identify Transcription Factor ◽

Specific Proteins ◽

Species Specific

The complex expression patterns observed for many genes are often regulated by distal transcription enhancers. Changes in the nucleotide sequences of enhancers may therefore lead to changes in gene expression, representing a central mechanism by which organisms evolve. With the development of the experimental technique of chromatin immunoprecipitation (ChIP), in which discrete regions of the genome bound by specific proteins can be identified, it is now possible to identify transcription factor binding events (putative cis -regulatory elements) in entire genomes. Comparing protein–DNA binding maps allows us, for the first time, to attempt to identify regulatory differences and infer global patterns of change in gene expression across species. Here, we review studies that used genome-wide ChIP to study the evolution of enhancers. The trend is one of high divergence of cis -regulatory elements between species, possibly compensated by extensive creation and loss of regulatory elements and rewiring of their target genes. We speculate on the meaning of the differences observed and discuss that although ChIP experiments identify the biochemical event of protein–DNA interaction, it cannot determine whether the event results in a biological function, and therefore more studies are required to establish the effect of divergence of binding events on species-specific gene expression.

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Upregulation of eIF4E in Nucleophosmin 1 (NPM1) Haploinsufficient Cells Alters CCAAT Enhancer Binding Protein Alpha (C/EBPα) Activity: Implications for MDS and AML

Blood ◽

10.1182/blood.v118.21.2432.2432 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2432-2432

Author(s):

Nirmalee Abayasekara ◽

Michelle Levine ◽

Niccolo Bolli ◽

Hong Sun ◽

Matthew Silver ◽

...

Keyword(s):

Gene Expression ◽

Translation Initiation ◽

Translational Control ◽

Conflicts Of Interest ◽

Mrna Translation ◽

Dominant Negative ◽

Full Length ◽

Initiation Factor ◽

Specific Gene ◽

Specific Gene Expression

Abstract Abstract 2432 NPM1, is a highly conserved, ubiquitous nucleolar phosphoprotein that belongs to the nucleoplasmin family of nuclear chaperones. NPM1−/− mice die at mid-gestation (E11.5) from anemia, underscoring the gene's role in embryonic development. NPM1 is one of the most frequently mutated genes in AML. Mutations in NPM1 are found in 50% of normal karyotype AML patients, and mutant NPM1 (NPMc+) is aberrantly located in the cytoplasm of leukemic blasts in about 35% of all AML patients. Furthermore, NPM1 maps to a region on chromosome 5q that is the target of deletions in both de novo and therapy-associated human MDS. NPM1 thus acts as a haploinsufficient tumor suppressor in the hematological compartment, although the mechanism of its contribution to dysmyelopoiesis remains unknown. NPM-1+/− mice develop a hematological syndrome similar to that observed in human MDS, and develop AML over time. The NPM1 deficient model therefore provides a platform to interrogate the molecular basis of MDS. We identified nucleophosmin (NPM1) in a screen for protein binding partners of C/EBPα. C/EBPα is a single exon gene, but is expressed as two isoforms that arise by alternate translation start sites to yield a full length C/EBPα p42 and a truncated dominant negative C/EBPα p30 isoform. Translational control of isoform expression is orchestrated by a conserved upstream open reading frame (uORF) in the 5' untranslated region (5'UTR) and modulated by the translation initiation factors eIF4E and eIF2. We generated factor-dependent myeloid cell lines from the bone marrow of Npm1+/+ and Npm1+/− mice. These lines are IL-3-dependent and inducible toward neutrophil maturation with GM-CSF and/ or all- trans retinoic acid (ATRA). Neutrophils derived from MNPM1+/− cells display defective neutrophil-specific gene expression, including a cassette of C/EBPα-dependent genes. These observations led us to postulate that myeloid abnormalities in NPM1 deficiency reflect an aberrant NPM1-C/EBPα axis. We show that NPM1 haploinsufficiency upregulates eIF4E (eukaryotic initiation factor 4E) (but not eIF2), which binds the mRNA-Cap (m7-GTP) as part of the mRNA translation initiation complex, eIF4F. Increased eIF4E is observed in about 30% of all malignancies. Initial increased eIF4E levels in MNPM+/− cells likely reflect transcriptional activation by the oncoprotein c-Myc, protein levels of which are also elevated in MNPM1+/− cells. We propose that increased eIF4E then induces increased C/EBPαp30 translation. C/EBPαp30 is a dominant negative inhibitor of full length C/EBPαp42 activity and disrupts normal neutrophil development. Furthermore, we demonstrate that C/EBPαp30 but not C/EBPαp42, activates the eIF4E promoter. We propose a positive feedback loop, wherein increased C/EBPαp30 induced by eIF4E further increases the expression of eIF4E. Our data suggest that NPM1 deficiency modulates neutrophil-specific gene expression by altering C/EBPα. We propose an aberrant feed-forward mechanism that increases levels of both eIF4E and C/EBPαp30 and likely contributes to MDS associated with NPM1 deficiency. Disclosures: No relevant conflicts of interest to declare.

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General decapping activators target different subsets of inefficiently translated mRNAs

10.1101/344937 ◽

2018 ◽

Cited By ~ 2

Author(s):

Feng He ◽

Alper Celik ◽

Allan Jacobson

Keyword(s):

Gene Expression ◽

Mrna Expression ◽

Mrna Translation ◽

Positive Regulation ◽

Mrna Decapping ◽

Terminal Domain ◽

Genome Wide ◽

Decapping Enzyme ◽

Partial Overlap

AbstractThe Dcp1-Dcp2 decapping enzyme and the decapping activators Pat1, Dhh1, and Lsm1 regulate mRNA decapping, but their mechanistic integration is unknown. We analyzed the gene expression consequences of deleting PAT1, LSM1, or DHH1, or the DCP2 C-terminal domain, and found that: i) the Dcp2 C-terminal domain is an effector of both negative and positive regulation; ii) rather than being global activators of decapping, Pat1, Lsm1, and Dhh1 directly target specific subsets of yeast mRNAs and loss of the functions of each of these factors has substantial indirect consequences for genome-wide mRNA expression; and iii) transcripts targeted by Pat1, Lsm1, and Dhh1 exhibit only partial overlap, are generally translated inefficiently, and, as expected, are targeted to decapping-dependent decay. Our results define the roles of Pat1, Lsm1, and Dhh1 in decapping of general mRNAs and suggest that these factors may monitor mRNA translation and target unique features of individual mRNAs.

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uORFs: Important Cis-Regulatory Elements in Plants

International Journal of Molecular Sciences ◽

10.3390/ijms21176238 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6238

Author(s):

Ting Zhang ◽

Anqi Wu ◽

Yaping Yue ◽

Yu Zhao

Keyword(s):

Gene Expression ◽

Translation Initiation ◽

Translational Control ◽

Translational Regulation ◽

Regulatory Elements ◽

Ribosome Profiling ◽

Open Reading Frames ◽

Post Translational Modification ◽

Cis Acting ◽

Eukaryotic Mrnas

Gene expression is regulated at many levels, including mRNA transcription, translation, and post-translational modification. Compared with transcriptional regulation, mRNA translational control is a more critical step in gene expression and allows for more rapid changes of encoded protein concentrations in cells. Translation is highly regulated by complex interactions between cis-acting elements and trans-acting factors. Initiation is not only the first phase of translation, but also the core of translational regulation, because it limits the rate of protein synthesis. As potent cis-regulatory elements in eukaryotic mRNAs, upstream open reading frames (uORFs) generally inhibit the translation initiation of downstream major ORFs (mORFs) through ribosome stalling. During the past few years, with the development of RNA-seq and ribosome profiling, functional uORFs have been identified and characterized in many organisms. Here, we review uORF identification, uORF classification, and uORF-mediated translation initiation. More importantly, we summarize the translational regulation of uORFs in plant metabolic pathways, morphogenesis, disease resistance, and nutrient absorption, which open up an avenue for precisely modulating the plant growth and development, as well as environmental adaption. Additionally, we also discuss prospective applications of uORFs in plant breeding.

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