Highly accessible AU-rich regions in 3’ untranslated regions are hotspots for binding of proteins and miRNAs

AbstractBackgroundMicroRNAs (miRNAs) are endogenous short non-coding RNAs involved in the regulation of gene expression at the post-transcriptional level typically by promoting destabilization or translational repression of target RNAs. Sometimes this regulation is absent or different, which likely is the result of interactions with other post-transcriptional factors, particularly RNA-binding proteins (RBPs). Despite the importance of the interactions between RBPs and miRNAs, little is known about how they affect post-transcriptional regulation in a global scale.ResultsIn this study, we have analyzed CLIP datasets of 49 RBPs in HEK293 cells with the aim of understanding the interplay between RBPs and miRNAs in post-transcriptional regulation. Our results show that RBPs bind preferentially in conserved regulatory hotspots that frequently contain miRNA target sites. This organization facilitates the competition and cooperation among RBPs and the regulation of miRNA target site accessibility. In some cases RBP enrichment on target sites correlates with miRNA expression, suggesting coordination between the regulatory factors. However, in most cases, competition among factors is the most plausible interpretation of our data. Upon AGO2 knockdown, transcripts that contain such hotspots that overlap target sites of expressed miRNAs in 3’UTRs are significantly less up-regulated than transcripts without them, suggesting that RBP binding limits miRNA accessibility.ConclusionsWe show that RBP binding is concentrated in regulatory hotspots in 3’UTRs. The presence of these hotspots facilitates the interaction among post-transcriptional regulators, that interact or compete with each other under different conditions. These hotspots are enriched in genes with regulatory functions such as DNA binding and RNA binding. Taken together, our results suggest that hotspots are important regulatory regions that define an extra layer of auto-regulatory control of post-transcriptional regulation.

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Targeting of Post-Transcriptional Regulation as Treatment Strategy in Acute Leukemia

10.5772/intechopen.94421 ◽

2020 ◽

Author(s):

Paulina Podszywalow-Bartnicka ◽

Magdalena Wolczyk ◽

Katarzyna Piwocka

Keyword(s):

Transcriptional Regulation ◽

Acute Leukemia ◽

Cancer Cells ◽

Rna Binding ◽

Rna Binding Proteins ◽

Protein Profile ◽

Cellular Protein ◽

Special Focus ◽

Transcriptional Level ◽

Post Transcriptional Regulation

Post-transcriptional regulation is an important step of gene expression that allows to fine-tune the cellular protein profile (so called proteome) according to the current demands. That mechanism has been developed to aid survival under stress conditions, however it occurs to be hijacked by cancer cells. Adjustment of the protein profile remodels signaling in cancer cells to adapt to therapeutic treatment, thereby enabling persistence despite unfavorable environment or accumulating mutations. The proteome is shaped at the post-transcriptional level by numerous mechanisms such as alternative splicing, mRNA modifications and triage by RNA binding proteins, change of ribosome composition or signaling, which altogether regulate the translation process. This chapter is an overview of the translation disturbances found in leukemia and their role in development of the disease, with special focus on the possible therapeutic strategies tested in acute leukemia which target elements of those regulatory mechanisms.

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

Cancers ◽

10.3390/cancers12061539 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1539 ◽

Cited By ~ 2

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.

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The architecture of the human RNA-binding protein regulatory network

10.1101/041426 ◽

2016 ◽

Cited By ~ 1

Author(s):

Alessandro Quattrone ◽

Erik Dassi

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Regulatory Network ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Hierarchical Structures ◽

Systematic Investigation ◽

Regulatory Structure ◽

Post Transcriptional Regulation

AbstractRNA-binding proteins (RBPs) are key players of post-transcriptional regulation of gene expression. These proteins influence both cellular physiology and pathology by regulating processes ranging from splicing and polyadenylation to mRNA localization, stability, and translation. To fine-tune the outcome of their regulatory action, RBPs rely on an intricate web of competitive and cooperative interactions. Several studies have described individual interactions of RBPs with RBP mRNAs, suggestive of a RBP-RBP regulatory structure. Here we present the first systematic investigation of this structure, based on a network including almost fifty thousand experimentally determined interactions between RBPs and bound RBP mRNAs.Our analysis identified two features defining the structure of the RBP-RBP regulatory network. What we call “RBP clusters” are groups of densely interconnected RBPs which co-regulate their targets, suggesting a tight control of cooperative and competitive behaviors. “RBP chains”, instead, are hierarchical structures driven by evolutionarily ancient RBPs, which connect the RBP clusters and could in this way provide the flexibility to coordinate the tuning of a broad set of biological processes.The combination of these two features suggests that RBP chains may use the modulation of their RBP targets to coordinately control the different cell programs controlled by the RBP clusters. Under this island-hopping model, the regulatory signal flowing through the chains hops from one RBP cluster to another, implementing elaborate regulatory plans to impact cellular phenotypes. This work thus establishes RBP-RBP interactions as a backbone driving post-transcriptional regulation of gene expression to allow the fine-grained control of RBPs and their targets.

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Distinct Hypoxia-induced Translational Profiles of Embryonic and Adult-derived Macrophages

10.1101/2021.03.18.435732 ◽

2021 ◽

Author(s):

Nicholas S. Wilcox ◽

Timur O. Yarovinsky ◽

Prakruti Pandya ◽

Vinod S. Ramgolam ◽

Albertomaria Moro ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Rna Binding ◽

Environmental Changes ◽

Rna Binding Proteins ◽

Fetal Liver ◽

Affinity Purification ◽

Regulation Of Gene Expression ◽

Translation Rate ◽

Post Transcriptional Regulation

SummaryTissue homeostasis and repair are orchestrated by resident and newly recruited macrophages that alter their gene expression program in response to changes in tissue microenvironment. Embryonic macrophages, such as fetal liver derived macrophages (FLDM) seed the organs, including heart and lung during embryonic development and persist throughout the adult lifetime, while bone marrow-derived macrophages (BMDM) are recruited following an acute perturbation. Transcriptome analyses of FLDM and BMDM identified differences between them at the level of RNA expression, which correlates imperfectly with protein levels. Post-transcriptional regulation by microRNAs (miRNAs) and RNA-binding proteins determines mRNA stability and translation rate and may override transcriptional cues in response to environmental changes, such as hypoxia. To identify distinct features of FLDM and BMDM response to hypoxia at the level of translation, we employed translating ribosome affinity purification (TRAP) to isolate polysomal RNA. RNA-seq profiling of translated RNA identified distinct hypoxia-induced translational signature of BMDM (Ly6e, vimentin and glycolysis-associated enzymes Pgk1, Tpi1, Aldoa, Ldha) and FLDM (chemokines Ccl7 and Ccl2). By translational profiling of BMDM and FLDM with deletion of the RNA-binding protein HuR, we identified transcripts that were dependent on HuR. These findings highlight the importance of HuR and identify its distinct targets for post-transcriptional regulation of gene expression in embryonic vs. adult-derived macrophages.

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Roles of RNA-binding Proteins and Post-transcriptional Regulation in Driving Male Germ Cell Development in the Mouse

Advances in Experimental Medicine and Biology - RNA Processing ◽

10.1007/978-3-319-29073-7_6 ◽

2016 ◽

pp. 123-151 ◽

Cited By ~ 13

Author(s):

Donny D. Licatalosi

Keyword(s):

Transcriptional Regulation ◽

Germ Cell ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cell Development ◽

Male Germ Cell ◽

Germ Cell Development ◽

Post Transcriptional Regulation

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Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control

Biochemistry and Cell Biology ◽

10.1139/bcb-2017-0310 ◽

2019 ◽

Vol 97 (1) ◽

pp. 10-20 ◽

Cited By ~ 7

Author(s):

Laura P.M.H. de Rooij ◽

Derek C.H. Chan ◽

Ava Keyvani Chahi ◽

Kristin J. Hope

Keyword(s):

Transcriptional Regulation ◽

Stem Cell ◽

Cell Fate ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Control Of Gene Expression ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Post Transcriptional Regulation

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved; however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA-binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation, or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSCs, its implications for normal, perturbed, and malignant hematopoiesis, and the most recent technological innovations aimed at RBP–RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

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Aberrant Post-Transcriptional Regulation of Protein Expression in the Development of Chronic Obstructive Pulmonary Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222111963 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11963

Author(s):

Noof Aloufi ◽

Aeshah Alluli ◽

David H. Eidelman ◽

Carolyn J. Baglole

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Transcriptional Regulation ◽

Pulmonary Disease ◽

Rna Binding ◽

Rna Binding Proteins ◽

Chronic Obstructive ◽

Respiratory Disorder ◽

Obstructive Pulmonary Disease ◽

Cellular Processes ◽

Post Transcriptional Regulation

Chronic obstructive pulmonary disease (COPD) is an incurable and prevalent respiratory disorder that is characterized by chronic inflammation and emphysema. COPD is primarily caused by cigarette smoke (CS). CS alters numerous cellular processes, including the post-transcriptional regulation of mRNAs. The identification of RNA-binding proteins (RBPs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as main factors engaged in the regulation of RNA biology opens the door to understanding their role in coordinating physiological cellular processes. Dysregulation of post-transcriptional regulation by foreign particles in CS may lead to the development of diseases such as COPD. Here we review current knowledge about post-transcriptional events that may be involved in the pathogenesis of COPD.

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