scholarly journals Genetic variants associated mRNA stability in lung

2021 ◽  
Author(s):  
Jian-Rong Li ◽  
Mabel Tang ◽  
Yafang Li ◽  
Christopher I Amos ◽  
Chao Cheng
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Mrna Stability ◽  
Genetic Variants ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Seq ◽  
Post Transcriptional Regulation ◽  
Gene Expression Levels

AbstractExpression quantitative trait loci (eQTLs) analyses have been widely used to identify genetic variants associated with gene expression levels to understand what molecular mechanisms underlie genetic traits. The resultant eQTLs might affect the expression of associated genes through transcriptional or post-transcriptional regulation. In this study, we attempt to distinguish these two types of regulation by identifying genetic variants associated with mRNA stability of genes (stQTLs). Specifically, we computationally inferred mRNA stability of genes based on RNA-seq data and performed association analysis to identify stQTLs. Using the Genotype-Tissue Expression (GTEx) lung RNA-Seq data, we identified a total of 142,801 stQTLs for 3,942 genes and 186,132 eQTLs for 4,751 genes from 15,122,700 genetic variants for 13,476 genes, respectively. Interesting, our results indicated that stQTLs were enriched in the CDS and 3’UTR regions, while eQTLs are enriched in the CDS, 3’UTR, 5’UTR, and upstream regions. We also found that stQTLs are more likely than eQTLs to overlap with RNA binding protein (RBP) and microRNA (miRNA) binding sites. Our analyses demonstrate that simultaneous identification of stQTLs and eQTLs can provide more mechanistic insight on the association between genetic variants and gene expression levels.Author SummaryIn the past decade, many studies have identified genetic variants associated with gene expression level (eQTLs) in different phenotypes, including tissues and diseases. Gene expression is the result of cooperation between transcriptional regulation, such as transcriptional activity, and post-transcriptional regulation, such as mRNA stability. Here, we present a computational framework that take advantage of recently developed methods to estimate mRNA stability from RNA-Seq, which is widely used to estimate gene expression, and then to identify genetic variants associated with mRNA stability (stQTLs) in lung tissue. Compared to eQTLs, we found that genetic variants that affects mRNA stability are more significantly located in the CDS and 3’UTR regions, which are known to interact with RNA-binding proteins (RBPs) or microRNAs to regulate stability. In addition, stQTLs are significantly more likely to overlap the binding sites of RBPs. We show that the six RBPs that most significantly bind to stQTLs are all known to regulate mRNA stability. This pipeline of simultaneously identifying eQTLs and stQTLs using only RNA-Seq data can provide higher resolution than traditional eQTLs study to better understand the molecular mechanisms of genetic variants on the regulation of gene expression.

scholarly journals Genetic Variants Associated mRNA Stability in Lung

2021 ◽  
Author(s):  
Jian-Rong Li ◽  
Mabel Tang ◽  
Yafang Li ◽  
Christopher I Amos ◽  
Chao Cheng
Keyword(s):  
Gene Expression ◽  
Mrna Stability ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Tissue Expression ◽  
Rna Seq ◽  
Genetic Traits ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract Background: Expression quantitative trait loci (eQTLs) analyses have been widely used to identify genetic variants associated with gene expression levels to understand what molecular mechanisms underlie genetic traits. The resultant eQTLs might affect the expression of associated genes through transcriptional or post-transcriptional regulation. In this study, we attempt to distinguish these two types of regulation by identifying genetic variants associated with mRNA stability of genes (stQTLs).Results: Here, we presented a computational framework that take the advantage of recently developed methods to infer the mRNA stability of genes based on RNA-seq data and performed association analysis to identify stQTLs. Using the Genotype-Tissue Expression (GTEx) lung RNA-Seq data, we identified a total of 142,801 stQTLs for 3,942 genes and 186,132 eQTLs for 4,751 genes from 15,122,700 genetic variants for 13,476 genes, respectively. Interesting, our results indicated that stQTLs were enriched in the CDS and 3’UTR regions, while eQTLs are enriched in the CDS, 3’UTR, 5’UTR, and upstream regions. We also found that stQTLs are more likely than eQTLs to overlap with RNA binding protein (RBP) and microRNA (miRNA) binding sites. Our analyses demonstrate that simultaneous identification of stQTLs and eQTLs can provide more mechanistic insight on the association between genetic variants and gene expression levels.

scholarly journals Regulatory signals in messenger RNA: determinants of nutrient–gene interaction and metabolic compartmentation

1998 ◽  
Vol 80 (4) ◽  
pp. 307-321
Author(s):  
John E. Hesketh ◽  
M. Helena Vasconcelos ◽  
Giovanna Bermano
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Mrna Stability ◽  
Transcriptional Control ◽  
Regulation Of Gene Expression ◽  
Untranslated Regions ◽  
Nutritional Requirements ◽  
Control Of Gene Expression ◽  
Metabolic Compartmentation ◽  
Post Transcriptional Regulation

Nutrition has marked influences on gene expression and an understanding of the interaction between nutrients and gene expression is important in order to provide a basis for determining the nutritional requirements on an individual basis. The effects of nutrition can be exerted at many stages between transcription of the genetic sequence and production of a functional protein. This review focuses on the role of post-transcriptional control, particularly mRNA stability, translation and localization, in the interactions of nutrients with gene expression. The effects of both macronutrients and micronutrients on regulation of gene expression by post-transcriptional mechanisms are presented and the post-transcriptional regulation of specific genes of nutritional relevance (glucose transporters, transferrin, selenoenzymes, metallothionein, lipoproteins) is described in detail. The function of the regulatory signals in the untranslated regions of the mRNA is highlighted in relation to control of mRNA stability, translation and localization and the importance of these mRNA regions to regulation by nutrients is illustrated by reference to specific examples. The localization of mRNA by signals in the untranslated regions and its function in the spatial organization of protein synthesis is described; the potential of such mechanisms to play a key part in nutrient channelling and metabolic compartmentation is discussed. It is concluded that nutrients can influence gene expression through control of the regulatory signals in these untranslated regions and that the post-transcriptional regulation of gene expression by these mechanisms may influence nutritional requirements. It is emphasized that in studies of nutritional control of gene expression it is important not to focus only on regulation through gene promoters but also to consider the possibility of post-transcriptional control.

Tumor protein D52 expression is post-transcriptionally regulated by T-cell intercellular antigen (TIA) 1 and TIA-related protein via mRNA stability

2017 ◽  
Vol 474 (10) ◽  
pp. 1669-1687
Author(s):  
Hiromi Motohashi ◽  
Yoshiki Mukudai ◽  
Chihiro Ito ◽  
Kosuke Kato ◽  
Toshikazu Shimane ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
T Cell ◽  
Growth Factor ◽  
Mrna Stability ◽  
Rna Binding ◽  
Rna Degradation ◽  
Related Protein ◽  
Binding Ability ◽  
Cis Acting ◽  
Post Transcriptional Regulation

Although tumor protein D52 (TPD52) family proteins were first identified nearly 20 years ago, their molecular regulatory mechanisms remain unclear. Therefore, we investigated the post-transcriptional regulation of TPD52 family genes. An RNA immunoprecipitation (RIP) assay showed the potential binding ability of TPD52 family mRNAs to several RNA-binding proteins, and an RNA degradation assay revealed that TPD52 is subject to more prominent post-transcriptional regulation than are TPD53 and TPD54. We subsequently focused on the 3′-untranslated region (3′-UTR) of TPD52 as a cis-acting element in post-transcriptional gene regulation. Several deletion mutants of the 3′-UTR of TPD52 mRNA were constructed and ligated to the 3′-end of a reporter green fluorescence protein gene. An RNA degradation assay revealed that a minimal cis-acting region, located in the 78-280 region of the 5′-proximal region of the 3′-UTR, stabilized the reporter mRNA. Biotin pull-down and RIP assays revealed specific binding of the region to T-cell intracellular antigen 1 (TIA-1) and TIA-1-related protein (TIAR). Knockdown of TIA-1/TIAR decreased not only the expression, but also the stability of TPD52 mRNA; it also decreased the expression and stability of the reporter gene ligated to the 3′-end of the 78-280 fragment. Stimulation of transforming growth factor-β and epidermal growth factor decreased the binding ability of these factors, resulting in decreased mRNA stability. These results indicate that the 78-280 fragment and TIA-1/TIAR concordantly contribute to mRNA stability as a cis-acting element and trans-acting factor(s), respectively. Thus, we here report the specific interactions between these elements in the post-transcriptional regulation of the TPD52 gene.

scholarly journals PSDX: A Comprehensive Multi-Omics Association Database of Populus trichocarpa With a Focus on the Secondary Growth in Response to Stresses

2021 ◽  
Vol 12 ◽  
Author(s):  
Huiyuan Wang ◽  
Sheng Liu ◽  
Xiufang Dai ◽  
Yongkang Yang ◽  
Yunjun Luo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Transcription Initiation ◽  
High Throughput Sequencing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Populus Trichocarpa ◽  
Secondary Growth ◽  
A Genome ◽  
Post Transcriptional Regulation

Populus trichocarpa (P. trichocarpa) is a model tree for the investigation of wood formation. In recent years, researchers have generated a large number of high-throughput sequencing data in P. trichocarpa. However, no comprehensive database that provides multi-omics associations for the investigation of secondary growth in response to diverse stresses has been reported. Therefore, we developed a public repository that presents comprehensive measurements of gene expression and post-transcriptional regulation by integrating 144 RNA-Seq, 33 ChIP-seq, and six single-molecule real-time (SMRT) isoform sequencing (Iso-seq) libraries prepared from tissues subjected to different stresses. All the samples from different studies were analyzed to obtain gene expression, co-expression network, and differentially expressed genes (DEG) using unified parameters, which allowed comparison of results from different studies and treatments. In addition to gene expression, we also identified and deposited pre-processed data about alternative splicing (AS), alternative polyadenylation (APA) and alternative transcription initiation (ATI). The post-transcriptional regulation, differential expression, and co-expression network datasets were integrated into a new P. trichocarpa Stem Differentiating Xylem (PSDX) database, which further highlights gene families of RNA-binding proteins and stress-related genes. The PSDX also provides tools for data query, visualization, a genome browser, and the BLAST option for sequence-based query. Much of the data is also available for bulk download. The availability of PSDX contributes to the research related to the secondary growth in response to stresses in P. trichocarpa, which will provide new insights that can be useful for the improvement of stress tolerance in woody plants.

scholarly journals Conceptual Advances in Control of Inflammation by the RNA-Binding Protein Tristetraprolin

2021 ◽  
Vol 12 ◽  
Author(s):  
Pavel Kovarik ◽  
Annika Bestehorn ◽  
Jeanne Fesselet
Keyword(s):  
Immune Responses ◽  
Mrna Stability ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Degradation ◽  
Decay Rates ◽  
Mrna Destabilization

Regulated changes in mRNA stability are critical drivers of gene expression adaptations to immunological cues. mRNA stability is controlled mainly by RNA-binding proteins (RBPs) which can directly cleave mRNA but more often act as adaptors for the recruitment of the RNA-degradation machinery. One of the most prominent RBPs with regulatory roles in the immune system is tristetraprolin (TTP). TTP targets mainly inflammation-associated mRNAs for degradation and is indispensable for the resolution of inflammation as well as the maintenance of immune homeostasis. Recent advances in the transcriptome-wide knowledge of mRNA expression and decay rates together with TTP binding sites in the target mRNAs revealed important limitations in our understanding of molecular mechanisms of TTP action. Such orthogonal analyses lead to the discovery that TTP binding destabilizes some bound mRNAs but not others in the same cell. Moreover, comparisons of various immune cells indicated that an mRNA can be destabilized by TTP in one cell type while it remains stable in a different cell linage despite the presence of TTP. The action of TTP extends from mRNA destabilization to inhibition of translation in a subset of targets. This article will discuss these unexpected context-dependent functions and their implications for the regulation of immune responses. Attention will be also payed to new insights into the role of TTP in physiology and tissue homeostasis.

scholarly journals The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1539 ◽  
Author(s):  
Yogesh Saini ◽  
Jian Chen ◽  
Sonika Patial
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Zinc Finger ◽  
Binding Proteins ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Finger Protein ◽  
Post Transcriptional Regulation

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

Essential Cytoplasmic Role of the Histone Lysine Methyltransferase Setdb1 in Post-Transcriptional Regulation in Embryonic Stem Cells

2021 ◽  
Author(s):  
Roberta Rapone ◽  
Laurence Del Maestro ◽  
Costas Bouyioukos ◽  
Sonia Albini ◽  
Paola Cruz-Tapias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Transcriptional Regulation ◽  
Mrna Stability ◽  
Regulation Of Gene Expression ◽  
Embryonic Stem ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Post Transcriptional Regulation

Abstract Embryonic stem cells (ESCs) fate is regulated both at transcriptional and post-transcriptional levels. Indeed, several studies showed that, in addition to gene transcription, mRNA stability and protein synthesis are finely tuned and strongly control the ESCs pluripotency and fate changes. An increasing number of RNA-binding proteins (RBPs) involved in post-transcriptional and translational regulation of gene expression has been identified as regulators of ESC identity. The major lysine methyltransferase Setdb1 is essential for the self-renewal and viability of ESCs. Setdb1 was primarily known to methylate the lysine 9 of histone 3 (H3K9) in the nucleus, where it regulates chromatin functions. However, Setdb1 is also massively localized in the cytoplasm, including in mouse ESCs, where its role remains unknown. Here we show that the cytoplasmic Setdb1 (cSetdb1) is essential for the survival of mESCs. Functional assays further demonstrate that cSetdb1 regulates gene expression post-transcriptionally, affecting the abundance of mRNAs and the rate of newly synthetized proteins. A yeast-two-hybrid assay shows that cSetdb1 interacts with several regulators of mRNA stability and protein translation machinery, such as the ESCs-specific E3 ubiquitin ligase and mRNA silencer Trim71/Lin41. Finally, proteomic analyses reveal that cSetdb1 is required for the integrity of Trim71 complexes involved in mRNA metabolism and translation. Altogether, our data uncover the essential cytoplasmic function of a firstly supposed nuclear “histone” lysine methyltransferase, Setdb1, and provide new insights into the cytoplasmic/post-transcriptional regulation of gene expression mediated by a key epigenetic regulator.

Post-transcriptional regulation of gene expression by Unr

2015 ◽  
Vol 43 (3) ◽  
pp. 323-327 ◽  
Author(s):  
Swagat Ray ◽  
Pól Ó Catnaigh ◽  
Emma C. Anderson
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Protein Interactions ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Negative Regulator ◽  
Cellular Translation ◽  
Cellular Mrnas ◽  
Internal Initiation ◽  
Post Transcriptional Regulation

Unr (upstream of N-ras) is a eukaryotic RNA-binding protein that has a number of roles in the post-transcriptional regulation of gene expression. Originally identified as an activator of internal initiation of picornavirus translation, it has since been shown to act as an activator and inhibitor of cellular translation and as a positive and negative regulator of mRNA stability, regulating cellular processes such as mitosis and apoptosis. The different post-transcriptional functions of Unr depend on the identity of its mRNA and protein partners and can vary with cell type and changing cellular conditions. Recent high-throughput analyses of RNA–protein interactions indicate that Unr binds to a large subset of cellular mRNAs, suggesting that Unr may play a wider role in translational responses to cellular signals than previously thought.

scholarly journals The Role of lncRNAs in Gene Expression Regulation through mRNA Stabilization

2021 ◽  
Vol 7 (1) ◽  
pp. 3
Author(s):  
Maialen Sebastian-delaCruz ◽  
Itziar Gonzalez-Moro ◽  
Ane Olazagoitia-Garmendia ◽  
Ainara Castellanos-Rubio ◽  
Izortze Santin
Keyword(s):  
Gene Expression ◽  
Mrna Stability ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Mrna Stabilization ◽  
Living Organisms ◽  
Almost All

mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide variety of biological processes and to maintain an appropriate cellular homeostasis. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of gene expression through different molecular mechanisms, including mRNA stabilization. In this review we provide an overview on the molecular mechanisms by which lncRNAs modulate mRNA stability and decay. We focus on how lncRNAs interact with RNA binding proteins and microRNAs to avoid mRNA degradation, and also on how lncRNAs modulate epitranscriptomic marks that directly impact on mRNA stability.

MicroRNAs Act as Decoy Molecules To Restore Granulocytic Maturation of Differentiation-Arrested BCR/ABL+ Myeloid Precursors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 31-31 ◽  
Author(s):  
Anna M. Eiring ◽  
Paolo Neviani ◽  
George A. Calin ◽  
Denis C. Roy ◽  
Carlo M. Croce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Myelogenous Leukemia ◽  
Imatinib Treatment ◽  
E2 Protein ◽  
Post Transcriptional Regulation

Abstract Altered microRNA (miR) expression contributes to aberrant post-transcriptional regulation of gene expression in different type of cancers; however, their role in the pathogenesis and progression of chronic myelogenous leukemia (CML) from chronic phase (CML-CP) to blast crisis (CML-BC) is still largely unknown. Microarray analysis of miR expression reveals that a discrete number of miRs are significantly upregulated (∼ 6.7% of the total 505 miRs present on the chip; 34 miRs) or downregulated (∼2.8% of the miRs present on the chip; 14 miRs) in an imatinib-sensitive manner in CML-BCCD34+ compared to CML-CPCD34+ progenitors and in BCR/ABL-expressing hematopoietic cell lines compared to untransformed parental cells. Among them, we focused our attention on miR-223, miR-15a/16-1 and miR-328, a microRNA with no currently known function, because of their importance in myelopoiesis, potential role as tumor suppressors and sequence homology with the 5’UTR of CEBPA mRNA, respectively. In 32D-BCR/ABL and K562 cells, Northern blot and TaqMan RT-PCR analyses revealed that expression of miR-223, miR-328, miR-15a and miR-16-1 was markedly suppressed (50–75% inhibition) by p210-BCR/ABL kinase activity and that imatinib treatment (1mM; 24h) restored the expression of these miRs to levels similar to those detected in non-transformed 32Dcl3 cells. Interestingly, sequence analysis of both miR-223 and miR-328 revealed homology with the hnRNP E2-binding site contained in the CEBPA uORF/spacer mRNA, a known target of the negative regulator of myeloid differentiation hnRNP E2. Accordingly, REMSA and UV-crosslinking experiments showed that synthetic miR-223 and to a greater extent miR-328 bind efficiently to recombinant hnRNP E2 protein and compete for its binding to an oligoribonucleotide containing the CEBPA uORF/spacer region, which is required for hnRNP E2-mediated translational inhibition of CEBPA in CML-BCCD34+ progenitors. Furthermore, both miR-223 and miR-328 bind endogenous hnRNP E2 from lysates of BCR/ABL-expressing but not parental cells, and from lysates of parental 32Dcl3 myeloid precursors ectopically expressing a Flag-tagged hnRNP E2 protein, suggesting that miR-223 and miR-328 may act as decoy molecules that interfere with the translation-inhibitory activity of hnRNP E2. Indeed, ectopic expression of miR-223 restored G-CSF-driven granulocytic maturation of differentiation-arrested 32D-BCR/ABL cells and restored C/EBPα expression, whereas it did not have any effect on cytokine-independent growth and clonogenic potential. Consistent with its ability to bind hnRNP E2, miR-328 also rescued C/EBPα expression and differentiation of cytokine-independent BCR/ABL-expressing myeloid precursor 32Dcl3 cells. By contrast, BCR/ABL-dependent colony formation was markedly reduced by overexpression of miR-15a and miR-16-1 (65–75% inhibition, P<0.001) and slightly decreased (40–50% inhibition, P<0.01) by ectopic miR-328 expression. Altogether, these data not only reinforce the importance of BCR/ABL-dependent post-transcriptional regulation of gene expression during CML disease progression but also suggest a new function for microRNAs as functional regulators of RNA binding proteins involved in the control of malignant cell growth, survival and differentiation.

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