Tristetraprolin: A cytosolic regulator of mRNA turnover moonlighting as transcriptional corepressor of gene expression

2021 ◽  
Author(s):  
Gabriel Rodríguez-Gómez ◽  
Alejandro Paredes-Villa ◽  
Mayte Guadalupe Cervantes-Badillo ◽  
Jessica Paola Gómez-Sonora ◽  
Jesús H. Jorge-Pérez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Turnover ◽  
Transcriptional Corepressor

scholarly journals HOS15 is a transcriptional corepressor of NPR1-mediated gene activation of plant immunity

2020 ◽  
Vol 117 (48) ◽  
pp. 30805-30815
Author(s):  
Mingzhe Shen ◽  
Chae Jin Lim ◽  
Junghoon Park ◽  
Jeong Eun Kim ◽  
Dongwon Baek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ubiquitin Ligase ◽  
Transcriptional Activation ◽  
Plant Immunity ◽  
Gene Activation ◽  
Transcriptional Corepressor ◽  
Defense Gene Expression ◽  
Dynamic Regulation ◽  
Defense Gene ◽  
Transcriptional Corepressors

Transcriptional regulation is a complex and pivotal process in living cells. HOS15 is a transcriptional corepressor. Although transcriptional repressors generally have been associated with inactive genes, increasing evidence indicates that, through poorly understood mechanisms, transcriptional corepressors also associate with actively transcribed genes. Here, we show that HOS15 is the substrate receptor for an SCF/CUL1 E3 ubiquitin ligase complex (SCFHOS15) that negatively regulates plant immunity by destabilizing transcriptional activation complexes containing NPR1 and associated transcriptional activators. In unchallenged conditions, HOS15 continuously eliminates NPR1 to prevent inappropriate defense gene expression. Upon defense activation, HOS15 preferentially associates with phosphorylated NPR1 to stimulate rapid degradation of transcriptionally active NPR1 and thus limit the extent of defense gene expression. Our findings indicate that HOS15-mediated ubiquitination and elimination of NPR1 produce effects contrary to those of CUL3-containing ubiquitin ligase that coactivate defense gene expression. Thus, HOS15 plays a key role in the dynamic regulation of pre- and postactivation host defense.

scholarly journals The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in C. elegans

2021 ◽  
Author(s):  
Josh Saul ◽  
Takashi Hirose ◽  
Robert Horvitz
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Transcriptional Corepressor ◽  
Cell Identity ◽  
C Elegans ◽  
Dna Binding Specificity ◽  
A Cell ◽  
Transcriptional Corepressors ◽  
And Function

Cell identity is characterized by a distinct combination of gene expression, cell morphology and cellular function established as progenitor cells divide and differentiate. Following establishment, cell identities can be unstable and require active and continuous maintenance throughout the remaining life of a cell. Mechanisms underlying the maintenance of cell identities are incompletely understood. Here we show that the gene ctbp-1, which encodes the transcriptional corepressor C-terminal binding protein-1 (CTBP-1), is essential for the maintenance of the identities of the two AIA interneurons in the nematode Caenorhabditis elegans. ctbp-1 is not required for the establishment of the AIA cell fate but rather functions cell-autonomously and can act in older worms to maintain proper AIA gene expression, morphology and function. From a screen for suppressors of the ctbp-1 mutant phenotype, we identified the gene egl-13, which encodes a SOX family transcription factor. We found that egl-13 regulates AIA function and aspects of AIA gene expression, but not AIA morphology. We conclude that the CTBP-1 protein maintains AIA cell identity in part by utilizing EGL-13 to repress transcriptional activity in the AIAs. More generally, we propose that transcriptional corepressors like CTBP-1 might be critical factors in the maintenance of cell identities, harnessing the DNA-binding specificity of transcription factors like EGL-13 to selectively regulate gene expression in a cell-specific manner.

scholarly journals Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Vasilisa Aksenova ◽  
Alexandra Smith ◽  
Hangnoh Lee ◽  
Prasanna Bhat ◽  
Caroline Esnault ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Export ◽  
Mrna Turnover ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Nucleocytoplasmic Trafficking ◽  
Cellular Functions ◽  
Pore Complexes ◽  
Slow Turnover

Abstract Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how individual nucleoporins act in these diverse processes. To address this question, we apply an Auxin-Induced Degron (AID) system to distinguish roles of basket nucleoporins NUP153, NUP50 and TPR. Acute depletion of TPR causes rapid and pronounced changes in transcriptomic profiles. These changes are dissimilar to shifts observed after loss of NUP153 or NUP50, but closely related to changes caused by depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) to NPCs and results in abnormal RNA transcription and export. Our findings demonstrate a unique and pivotal role of TPR in gene expression through TREX-2- and/or NXF1-dependent mRNA turnover.

scholarly journals Interrogating the degradation pathways of unstable mRNAs with XRN1-resistant sequences

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Volker Boehm ◽  
Jennifer V. Gerbracht ◽  
Marie-Charlotte Marx ◽  
Niels H. Gehring
Keyword(s):  
Gene Expression ◽  
Mrna Decay ◽  
Mrna Degradation ◽  
Eukaryotic Cells ◽  
Mrna Turnover ◽  
Degradation Pathways ◽  
Messenger Rnas ◽  
Endonucleolytic Cleavage ◽  
Nonsense Mediated Mrna Decay ◽  
Cytokine Mrnas

Abstract The turnover of messenger RNAs (mRNAs) is a key regulatory step of gene expression in eukaryotic cells. Due to the complexity of the mammalian degradation machinery, the contribution of decay factors to the directionality of mRNA decay is poorly understood. Here we characterize a molecular tool to interrogate mRNA turnover via the detection of XRN1-resistant decay fragments (xrFrag). Using nonsense-mediated mRNA decay (NMD) as a model pathway, we establish xrFrag analysis as a robust indicator of accelerated 5′–3′ mRNA decay. In tethering assays, monitoring xrFrag accumulation allows to distinguish decapping and endocleavage activities from deadenylation. Moreover, xrFrag analysis of mRNA degradation induced by miRNAs, AU-rich elements (AREs) as well as the 3′ UTRs of cytokine mRNAs reveals the contribution of 5′–3′ decay and endonucleolytic cleavage. Our work uncovers formerly unrecognized modes of mRNA turnover and establishes xrFrag as a powerful tool for RNA decay analyses.

scholarly journals Dynamic profiling of mRNA turnover reveals gene-specific and system-wide regulation of mRNA decay

2011 ◽  
Vol 22 (15) ◽  
pp. 2787-2795 ◽  
Author(s):  
Sarah E. Munchel ◽  
Ryan K. Shultzaberger ◽  
Naoki Takizawa ◽  
Karsten Weis
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Mrna Decay ◽  
Global Analysis ◽  
Decay Rates ◽  
Mrna Turnover ◽  
Control Of Gene Expression ◽  
Mrna Stabilization ◽  
Highly Sensitive ◽  
Wide Range

RNA levels are determined by the rates of both transcription and decay, and a mechanistic understanding of the complex networks regulating gene expression requires methods that allow dynamic measurements of transcription and decay in living cells with minimal perturbation. Here, we describe a metabolic pulse-chase labeling protocol using 4-thiouracil combined with large-scale RNA sequencing to determine decay rates of all mRNAs in Saccharomyces cerevisiae. Profiling in various growth and stress conditions reveals that mRNA turnover is highly regulated both for specific groups of transcripts and at the system-wide level. For example, acute glucose starvation induces global mRNA stabilization but increases the degradation of all 132 detected ribosomal protein mRNAs. This effect is transient and can be mimicked by inhibiting the target-of-rapamycin kinase. Half-lives of mRNAs critical for galactose (GAL) metabolism are also highly sensitive to changes in carbon source. The fast reduction of GAL transcripts in glucose requires their dramatically enhanced turnover, highlighting the importance of mRNA decay in the control of gene expression. The approach described here provides a general platform for the global analysis of mRNA turnover and transcription and can be applied to dissect gene expression programs in a wide range of organisms and conditions.

scholarly journals Codon choice directs constitutive mRNA levels in trypanosomes

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Janaina de Freitas Nascimento ◽  
Steven Kelly ◽  
Jack Sunter ◽  
Mark Carrington
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Open Reading Frame ◽  
Mrna Turnover ◽  
Mrna Levels ◽  
Protein Coding ◽  
Reading Frame ◽  
Protein Coding Genes ◽  
The Relationship ◽  
Adaptation Index

Selective transcription of individual protein coding genes does not occur in trypanosomes and the cellular copy number of each mRNA must be determined post-transcriptionally. Here, we provide evidence that codon choice directs the levels of constitutively expressed mRNAs. First, a novel codon usage metric, the gene expression codon adaptation index (geCAI), was developed that maximised the relationship between codon choice and the measured abundance for a transcriptome. Second, geCAI predictions of mRNA levels were tested using differently coded GFP transgenes and were successful over a 25-fold range, similar to the variation in endogenous mRNAs. Third, translation was necessary for the accelerated mRNA turnover resulting from codon choice. Thus, in trypanosomes, the information determining the levels of most mRNAs resides in the open reading frame and translation is required to access this information.

Impact of high pH stress on yeast gene expression: A comprehensive analysis of mRNA turnover during stress responses

2015 ◽  
Vol 1849 (6) ◽  
pp. 653-664 ◽  
Author(s):  
David Canadell ◽  
José García-Martínez ◽  
Paula Alepuz ◽  
José E. Pérez-Ortín ◽  
Joaquín Ariño
Keyword(s):  
Gene Expression ◽  
Stress Responses ◽  
Comprehensive Analysis ◽  
Mrna Turnover ◽  
Yeast Gene ◽  
High Ph ◽  
Ph Stress

scholarly journals Global Analysis of Pub1p Targets Reveals a Coordinate Control of Gene Expression through Modulation of Binding and Stability

2005 ◽  
Vol 25 (13) ◽  
pp. 5499-5513 ◽  
Author(s):  
Radharani Duttagupta ◽  
Bin Tian ◽  
Carol J. Wilusz ◽  
Danny T. Khounh ◽  
Patricia Soteropoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Global Analysis ◽  
Affinity Purification ◽  
Mrna Turnover ◽  
Sequence Motifs ◽  
Posttranscriptional Control ◽  
Control Of Gene Expression ◽  
Transcript Stability ◽  
Distinct Sequence

ABSTRACT Regulation of mRNA turnover is an important cellular strategy for posttranscriptional control of gene expression, mediated by the interplay of cis-acting sequences and associated trans-acting factors. Pub1p, an ELAV-like yeast RNA-binding protein with homology to T-cell internal antigen 1 (TIA-1)/TIA-1-related protein (TIAR), is an important modulator of the decay of two known classes of mRNA. Our goal in this study was to determine the range of mRNAs whose stability is dependent on Pub1p, as well as to identify specific transcripts that directly bind to this protein. We have examined global mRNA turnover in isogenic PUB1 and pub1Δ strains through gene expression analysis and demonstrate that 573 genes exhibit a significant reduction in half-life in a pub1Δ strain. We also examine the binding specificity of Pub1p using affinity purification followed by microarray analysis to comprehensively distinguish between direct and indirect targets and find that Pub1p significantly binds to 368 cellular transcripts. Among the Pub1p-associated mRNAs, 53 transcripts encoding proteins involved in ribosomal biogenesis and cellular metabolism are selectively destabilized in the pub1Δ strain. In contrast, genes involved in transporter activity demonstrate association with Pub1p but display no measurable changes in transcript stability. Characterization of two candidate genes, SEC53 and RPS16B, demonstrate that both Pub1p-dependent regulation of stability and Pub1p binding require 3′ untranslated regions, which harbor distinct sequence motifs. These results suggest that Pub1p binds to discrete subsets of cellular transcripts and posttranscriptionally regulates their expression at multiple levels.

scholarly journals The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid–induced myeloid gene expression and differentiation in acute myeloid leukemia

2020 ◽  
Vol 295 (27) ◽  
pp. 8887-8900
Author(s):  
Nickolas Steinauer ◽  
Chun Guo ◽  
Jinsong Zhang
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
Target Gene ◽  
Retinoic Acid Receptor ◽  
Inhibitory Effect ◽  
Myeloid Differentiation ◽  
Transcriptional Corepressor ◽  
Acute Myeloid

CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3, also known as MTG16 or ETO2) is a myeloid translocation gene family protein that functions as a master transcriptional corepressor in hematopoiesis. Recently, it has been shown that CBFA2T3 maintains leukemia stem cell gene expression and promotes relapse in acute myeloid leukemia (AML). However, a role for CBFA2T3 in myeloid differentiation of AML has not been reported. Here, we show that CBFA2T3 represses retinoic acid receptor (RAR) target gene expression and inhibits all-trans-retinoic acid (ATRA)-induced myeloid differentiation of AML cells. ChIP-Seq revealed that CBFA2T3 targets the RARα/RXRα cistrome in U937 AML cells, predominantly at myeloid-specific enhancers associated with terminal differentiation. CRISPR/Cas9-mediated abrogation of CBFA2T3 resulted in spontaneous and ATRA-induced activation of myeloid-specific genes in a manner correlated with myeloid differentiation. Importantly, these effects were reversed by CBFA2T3 re-expression. Mechanistic studies showed that CBFA2T3 inhibits RAR target gene transcription by acting at an early step to regulate histone acetyltransferase recruitment, histone acetylation, and chromatin accessibility at RARα target sites, independently of the downstream, RAR-mediated steps of transcription. Finally, we validated the inhibitory effect of CBFA2T3 on RAR in multiple AML subtypes and patient samples. To our knowledge, this is the first study to show that CBFA2T3 down-regulation is both necessary and sufficient for enhancing ATRA-induced myeloid gene expression and differentiation of AML cells. Our findings suggest that CBFA2T3 can serve as a potential target for enhancing AML responsiveness to ATRA differentiation therapies.

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