scholarly journals Dietary restriction induces posttranscriptional regulation of longevity genes

2019 ◽  
Vol 2 (4) ◽  
pp. e201800281 ◽  
Author(s):  
Jarod A Rollins ◽  
Dan Shaffer ◽  
Santina S Snow ◽  
Pankaj Kapahi ◽  
Aric N Rogers
Keyword(s):  
Life Span ◽  
Dietary Restriction ◽  
Posttranscriptional Regulation ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intron Retention ◽  
Translation Efficiency ◽  
Nonsense Mediated Decay ◽  
Longevity Genes

Dietary restriction (DR) increases life span through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome of Caenorhabditis elegans subjected to DR. Transcription of muscle regulatory and structural genes increased, whereas increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of posttranscriptional regulation identified putative roles for RNA-binding proteins, RNA editing, miRNA, alternative splicing, and nonsense-mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate life span. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally down-regulated genes. Furthermore, 3′ UTR editing and intron retention increase under DR and correlate with diminished translation, whereas trans-spliced genes are refractory to reduced translation efficiency compared with messages with the native 5′ UTR. Finally, we find that smg-6 and smg-7, which are genes governing selection and turnover of nonsense-mediated decay targets, are required for increased life span under DR.

scholarly journals Dietary restriction induces post-transcriptional regulation of longevity genes

2019 ◽  
Author(s):  
Jarod A. Rollins ◽  
Santina S. Snow ◽  
Pankaj Kapahi ◽  
Aric N. Rogers
Keyword(s):  
Transcriptional Regulation ◽  
Dietary Restriction ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intron Retention ◽  
Translation Efficiency ◽  
Nonsense Mediated Decay ◽  
Longevity Genes ◽  
Post Transcriptional Regulation

AbstractDietary restriction increases lifespan through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome of C. elegans subjected to dietary restriction. Transcription of muscle regulatory and structural genes increased, while increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of post-transcriptional regulation identified putative roles for RNA binding proteins, RNA editing, microRNA, alternative splicing, and nonsense mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate lifespan. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally downregulated genes. Furthermore, 3’ UTR editing and intron retention increase under dietary restriction and correlate with diminished translation, while trans-spliced genes are refractory to reduced translation efficiency compared to messages with the native 5’ UTR. Finally, we find that smg-6 and smg-7, which are genes governing selection and turnover of nonsense mediated decay targets, are required for increased lifespan under dietary restriction.

scholarly journals Neurogenesis: Regulation by Alternative Splicing and Related Posttranscriptional Processes

2016 ◽  
Vol 23 (5) ◽  
pp. 466-477 ◽  
Author(s):  
Enrique Lara-Pezzi ◽  
Manuel Desco ◽  
Alberto Gatto ◽  
María Victoria Gómez-Gaviro
Keyword(s):  
Alternative Splicing ◽  
Protein Function ◽  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Degradation ◽  
Protein Isoforms ◽  
Mammalian Brain ◽  
Nonsense Mediated Decay

The complexity of the mammalian brain requires highly specialized protein function and diversity. As neurons differentiate and the neuronal circuitry is established, several mRNAs undergo alternative splicing and other posttranscriptional changes that expand the variety of protein isoforms produced. Recent advances are beginning to shed light on the molecular mechanisms that regulate isoform switching during neurogenesis and the role played by specific RNA binding proteins in this process. Neurogenesis and neuronal wiring were recently shown to also be regulated by RNA degradation through nonsense-mediated decay. An additional layer of regulatory complexity in these biological processes is the interplay between alternative splicing and long noncoding RNAs. Dysregulation of posttranscriptional regulation results in defective neuronal differentiation and/or synaptic connections that lead to neurodevelopmental and psychiatric disorders.

scholarly journals Posttranscriptional regulation of intestinal epithelial cell repair by RNA binding protein IMP1

2018 ◽  
Author(s):  
Priya Chatterji ◽  
Kelly A. Whelan ◽  
Sarah F. Andres ◽  
Fernando C. Samper ◽  
Lauren A. Simon ◽  
...  
Keyword(s):  
Posttranscriptional Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Enhanced Recovery ◽  
Ribosome Profiling ◽  
Translation Efficiency ◽  
Intestinal Epithelial ◽  
Growth Defects ◽  
Direct Binding ◽  
Biochemical Analyses

AbstractRNA binding proteins, such as IMP1, are emerging as essential regulators of intestinal development and cancer. IMP1 hypomorphic mice exhibit severe intestinal growth defects, yet it’s role in adult intestinal epithelium is unclear. We employed ribosome profiling to test the effect of IMP1 loss on the “translatome” in colon cancer cell lines. In parallel, we evaluated mice with intestinal epithelial-specific Imp1 deletion (Imp1ΔIEC) following irradiation or colitis models. Ribosome-profiling revealed translation efficiency changes for multiple pathways important for intestinal homeostasis, including autophagy, in IMP1 knockout cells. We found increased autophagy flux in Imp1ΔIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts MAP1LC3B and ATG3. We found that Imp1ΔIEC mice exhibit enhanced recovery following irradiation, which is attenuated with genetic deletion of autophagy gene Atg7. Finally, we demonstrated that IMP1 is upregulated in Crohn’s disease patients and Imp1 loss lessened colitis severity in mice. These studies demonstrate that IMP1 acts as a posttranscriptional regulator of gut epithelial repair post-irradiation and colitis, in part through modulation of autophagy.

scholarly journals Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

2021 ◽  
pp. 1-6
Author(s):  
Miriam C. Aziz ◽  
Patricia N. Schneider ◽  
Gemma L. Carvill
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Nonsense Mediated Decay ◽  
Subsequent Degradation ◽  
Alternative Splicing Events ◽  
Genetic Epilepsies

Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic <i>SCN1A</i> variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

scholarly journals Posttranscriptional regulation of lipid metabolism by non-coding RNAs and RNA binding proteins

2018 ◽  
Vol 81 ◽  
pp. 129-140 ◽  
Author(s):  
Abhishek K. Singh ◽  
Binod Aryal ◽  
Xinbo Zhang ◽  
Yuhua Fan ◽  
Nathan L. Price ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Posttranscriptional Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Non Coding Rnas

scholarly journals The RNA-binding protein ELAVL1/HuR is essential for mouse spermatogenesis, acting both at meiotic and postmeiotic stages

2011 ◽  
Vol 22 (16) ◽  
pp. 2875-2885 ◽  
Author(s):  
Mai Nguyen Chi ◽  
Jacques Auriol ◽  
Bernard Jégou ◽  
Dimitris L. Kontoyiannis ◽  
James M.A. Turner ◽  
...  
Keyword(s):  
Germ Cells ◽  
Posttranscriptional Regulation ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Female Sterility ◽  
Targeted Deletion

Posttranscriptional mechanisms are crucial to regulate spermatogenesis. Accurate protein synthesis during germ cell development relies on RNA binding proteins that control the storage, stability, and translation of mRNAs in a tightly and temporally regulated manner. Here, we focused on the RNA binding protein Embryonic Lethal Abnormal Vision (ELAV) L1/Human antigen R (HuR) known to be a key regulator of posttranscriptional regulation in somatic cells but the function of which during gametogenesis has never been investigated. In this study, we have used conditional loss- and gain-of-function approaches to address this issue in mice. We show that targeted deletion of HuR specifically in germ cells leads to male but not female sterility. Mutant males are azoospermic because of the extensive death of spermatocytes at meiotic divisions and failure of spermatid elongation. The latter defect is also observed upon HuR overexpression. To elucidate further the molecular mechanisms underlying spermatogenesis defects in HuR-deleted and -overexpressing testes, we undertook a target gene approach and discovered that heat shock protein (HSP)A2/HSP70-2, a crucial regulator of spermatogenesis, was down-regulated in both situations. HuR specifically binds hspa2 mRNA and controls its expression at the translational level in germ cells. Our study provides the first genetic evidence of HuR involvement during spermatogenesis and reveals Hspa2 as a target for HuR.

scholarly journals Coordination of RNA Processing Regulation by Signal Transduction Pathways

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1475
Author(s):  
Veronica Ruta ◽  
Vittoria Pagliarini ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Rna Processing ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Signal Transduction Pathways ◽  
Challenges And Opportunities ◽  
Common Signal

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.

MiRNA:RBP Interplay as a Key Regulatory Element in Health and Disease

2020 ◽  
Vol 14 (02) ◽  
pp. 123-143
Author(s):  
Marcos G. Teneche ◽  
Neus Carbó ◽  
F. Javier Casado
Keyword(s):  
Neuronal Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Element ◽  
Mirna Biogenesis ◽  
Translation Efficiency ◽  
Stem Cell Maintenance ◽  
Physiological Processes ◽  
Health And Disease ◽  
Obesity And Cancer

Numerous crosstalk interactions between RNA-binding proteins (RBPs) and microRNAs (miRNAs) have been recently reported, unveiling the complexity and importance of gene expression modulation in health and disease. They control physiological processes such as stem cell maintenance, neuronal development or energetic metabolism, but are also responsible for pathological conditions, such as muscle waste and dystrophies, atherosclerosis, obesity and cancer. MiRNAs and RBPs are two of the well-studied post-transcriptional regulators and they may even reciprocally regulate themselves. MiRNAs can act on RBPs expression while RBPs modulate miRNA biogenesis, function and degradation. RBPs and miRNAs modulate mRNA expression at different levels, affecting their stability, splicing and translation efficiency through either competition for overlapping binding or modulation of mRNA structure by binding, but several other forms of interaction have been described. In this review, we will address the current bibliography regarding miRNA:RBP interactions and crosstalk events as well as their implications in health and disease.

scholarly journals Regulation, diversity and function of MECP2 exon and 3′UTR isoforms

2020 ◽  
Vol 29 (R1) ◽  
pp. R89-R99
Author(s):  
Deivid Carvalho Rodrigues ◽  
Marat Mufteev ◽  
James Ellis
Keyword(s):  
Dna Binding ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Alternative Polyadenylation ◽  
Cell Types ◽  
Protein Isoforms ◽  
Translation Efficiency ◽  
Mrna Isoforms ◽  
Exon 2 ◽  
Messenger Ribonucleic Acid

Abstract The methyl-CpG-binding protein 2 (MECP2) is a critical global regulator of gene expression. Mutations in MECP2 cause neurodevelopmental disorders including Rett syndrome (RTT). MECP2 exon 2 is spliced into two alternative messenger ribonucleic acid (mRNA) isoforms encoding MECP2-E1 or MECP2-E2 protein isoforms that differ in their N-termini. MECP2-E2, isolated first, was used to define the general roles of MECP2 in methyl-deoxyribonucleic acid (DNA) binding, targeting of transcriptional regulatory complexes, and its disease-causing impact in RTT. It was later found that MECP2-E1 is the most abundant isoform in the brain and its exon 1 is also mutated in RTT. MECP2 transcripts undergo alternative polyadenylation generating mRNAs with four possible 3′untranslated region (UTR) lengths ranging from 130 to 8600 nt. Together, the exon and 3′UTR isoforms display remarkable abundance disparity across cell types and tissues during development. These findings indicate discrete means of regulation and suggest that protein isoforms perform non-overlapping roles. Multiple regulatory programs have been explored to explain these disparities. DNA methylation patterns of the MECP2 promoter and first intron impact MECP2-E1 and E2 isoform levels. Networks of microRNAs and RNA-binding proteins also post-transcriptionally regulate the stability and translation efficiency of MECP2 3′UTR isoforms. Finally, distinctions in biophysical properties in the N-termini between MECP2-E1 and E2 lead to variable protein stabilities and DNA binding dynamics. This review describes the steps taken from the discovery of MECP2, the description of its key functions, and its association with RTT, to the emergence of evidence revealing how MECP2 isoforms are differentially regulated at the transcriptional, post-transcriptional and post-translational levels.

Sign in / Sign up

Export Citation Format

Share Document