scholarly journals Dynamic expression of tRNA-derived small RNAs define cellular states

2017 ◽  
Author(s):  
Daniel GR Yim ◽  
Srikar Krishna ◽  
Vairavan Lakshmanan ◽  
Judice LY Koh ◽  
Jung Eun Park ◽  
...  
Keyword(s):  
Small Rnas ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Functional Characterization ◽  
Embryonic Stem ◽  
Protein Translation ◽  
State Transitions ◽  
Cell State ◽  
Normal States ◽  
Factor C

AbstractTransfer RNA (tRNA)-derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell-state transitions remain unclear. Here we report the identification of a set of tsRNAs upregulated in differentiating mouse embryonic stem cells (mESCs). Mechanistic analyses revealed primary functions of tsRNAs in regulating polysome assembly and translation. Notably, interactome studies with differentially-enriched tsRNAs revealed a switch in associations with ‘effector’ RNPs and ‘target’ mRNAs in different cell-states. We also demonstrate that a specific pool of tsRNAs can interact with Igf2bp1, an RNA-binding protein, to influence the expression of the pluripotency-promoting factor-c-Myc, thereby providing evidence for tsRNAs in modulating stem cell-states in mESCs. Finally, tsRNA expression analyses in distinct, heterologous cell and tissue models of stem/transformed versus differentiated/normal states reveal that tsRNA-mediated regulation of protein translation may represent a global biological phenomenon associated with cell-state transitions.One Sentence SummaryIdentification and functional characterization of tRNA-derived small RNAs (tsRNAs) in cell state switches.

scholarly journals Systematic discovery of endogenous human ribonucleoprotein complexes

2018 ◽  
Author(s):  
Anna L. Mallam ◽  
Wisath Sae-Lee ◽  
Jeffrey M. Schaub ◽  
Fan Tu ◽  
Anna Battenhouse ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Complexes ◽  
Embryonic Stem ◽  
Human Protein ◽  
Disease States ◽  
Ribonucleoprotein Complexes ◽  
Associated Proteins ◽  
Domains Of Life ◽  
Factor C

AbstractRNA-binding proteins (RBPs) play essential roles in biology and are frequently associated with human disease. While recent studies have systematically identified individual RBPs, their higher order assembly intoRibonucleoprotein (RNP) complexes has not been systematically investigated. Here, we describe a proteomics method for systematic identification of RNP complexes in human cells. We identify 1,428 protein complexes that associate with RNA, indicating that over 20% of known human protein complexes contain RNA. To explore the role of RNA in the assembly of each complex, we identify complexes that dissociate, change composition, or form stable protein-only complexes in the absence of RNA. Importantly, these data also provide specific novel insights into the function of well-studied protein complexes not previously known to associate with RNA, including replication factor C (RFC) and cytokinetic centralspindlin complex. Finally, we use our method to systematically identify cell-type specific RNA-associated proteins in mouse embryonic stem cells. We distribute these data as a resource, rna.MAP (rna.proteincomplexes.org) which provides a comprehensive dataset for the study of RNA-associated protein complexes. Our system thus provides a novel methodology for further explorations across human tissues and disease states, as well as throughout all domains of life.SummaryAn exploration of human protein complexes in the presence and absence of RNA reveals endogenous ribonucleoprotein complexes

P5398CircRNAs deregulation in heart failure patients

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Greco ◽  
A Made' ◽  
M Longo ◽  
R Tikhomirov ◽  
S Castelvecchio ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Functional Characterization ◽  
Enrichment Analysis ◽  
Host Gene ◽  
Circular Rnas ◽  
Amplification Efficiency ◽  
Rna Seq ◽  
Bioinformatics Pipeline

Abstract Background Circular RNAs (circRNAs) are an emerging class of noncoding RNAs stemming from the splicing and circularization of pre-mRNAs exons. CircRNAs can regulate transcription and splicing, sequester microRNAs acting as “sponge” and inducing the respective targets, and bind to RNA binding proteins. Recently, they have been found deregulated in dilated cardiomyopathies (DCM), one of the cardiovascular diseases with the worst rate of morbidity and mortality, and whose molecular mechanisms are only partially known. Purpose Therein, we will evaluate in ischemic DCM patients the modulation of 17 circRNAs, 14 out of them obtained from literature data on DCM ischemic or not, while the other 3 were circRNAs not characterized in the heart previously. The study aims to identify circRNAs candidates for further functional characterization in DCM. In addition, as differential expression (DE) analysis is not easily performed for circRNAs in RNA-seq datasets, the validated circRNAs will be used to set up the most specific and sensitive bioinformatics pipeline for circRNA-DE analysis. Methods We designed divergent and convergent specific primers for 17 circRNAs and their host gene, respectively, and their amplification efficiency was measured by RT-qPCR. Transcripts expression was measured in left ventricle biopsies of 12 patients affected by non end-stage ischemic HF and of 12 matched controls. Results We identified cPVT1, cANKRD17, cBPTF as DE, and validated the modulation of 5 out of the 14 DCM-related circRNAs (cHIPK3, cALPK2, cPCMTD1, cNEBL, cSLC8A1), while cPDRM5, cTTN1 showed opposite modulation, which may be due to the specific disease condition. All of them were modulated differently from the respective host gene. CircRNA/miRNA interactions were predicted using Starbase 3.0. Next, mRNAs-targets of the identified miRNAs were predicted by mirDIP 4.1 and intersected with gene expression datasets of the same patients, previously obtained by microarray analysis. We found that cBPTF and cANKRD17 might sponge 12 and 2 miRNAs, respectively. Enrichment analysis of the relevant targets identified several important pathways implicated in DCM, such as MAPK, FoxO, EGFR, VEGF and Insulin/IGF pathways. In addition, deep RNA-Seq analysis that is currently ongoing and the validated circRNAs will be used to optimize the bioinformatics pipeline for circRNA DE analysis. Conclusions We identified a subset of circRNAs deregulated in ischemic HF potentially implicated in HF pathogenesis.

scholarly journals Single-Cell Genomics: Catalyst for Cell Fate Engineering

2021 ◽  
Vol 9 ◽  
Author(s):  
Boxun Li ◽  
Gary C. Hon
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
State Transitions ◽  
Small Scale ◽  
Specific Cell ◽  
Direct Reprogramming ◽  
Cell State

As we near a complete catalog of mammalian cell types, the capability to engineer specific cell types on demand would transform biomedical research and regenerative medicine. However, the current pace of discovering new cell types far outstrips our ability to engineer them. One attractive strategy for cellular engineering is direct reprogramming, where induction of specific transcription factor (TF) cocktails orchestrates cell state transitions. Here, we review the foundational studies of TF-mediated reprogramming in the context of a general framework for cell fate engineering, which consists of: discovering new reprogramming cocktails, assessing engineered cells, and revealing molecular mechanisms. Traditional bulk reprogramming methods established a strong foundation for TF-mediated reprogramming, but were limited by their small scale and difficulty resolving cellular heterogeneity. Recently, single-cell technologies have overcome these challenges to rapidly accelerate progress in cell fate engineering. In the next decade, we anticipate that these tools will enable unprecedented control of cell state.

scholarly journals Transite: A computational motif-based analysis platform that identifies RNA-binding proteins modulating changes in gene expression

2018 ◽  
Author(s):  
Konstantin Krismer ◽  
Shohreh Varmeh ◽  
Molly A. Bird ◽  
Anna Gattinger ◽  
Yi Wen Kong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Protein Translation ◽  
State Transitions ◽  
Global Changes ◽  
Expression Data ◽  
Platinum Based Chemotherapy

AbstractRNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. In response to various stimuli, alterations in RBP function contribute to global changes in gene expression, but identifying which specific RBPs are responsible for the observed changes in gene expression patterns remains an unmet need. Here, we presentTransitea multi-pronged computational approach that systematically infers RBPs influencing gene expression changes through alterations in RNA stability and degradation. As a proof of principle, we applied Transite to public RNA expression data from human patients with non-small cell lung cancer whose tumors were sampled at diagnosis, or after recurrence following treatment with platinum-based chemotherapy. Transite implicated known RBP regulators of the DNA damage response and identified hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a generalizable framework for the identification of RBPs responsible for gene expression changes that drive cell-state transitions and adds additional value to the vast wealth of publicly-available gene expression data.

scholarly journals Insights into the molecular mechanisms of cell fate decision making processes from chromosome structural dynamics

2021 ◽  
Author(s):  
Xiakun Chu ◽  
Jin Wang
Keyword(s):  
Decision Making ◽  
Cell Fate ◽  
Structural Dynamics ◽  
Normal Cell ◽  
Molecular Mechanisms ◽  
State Transitions ◽  
Cell Fate Decision ◽  
Cell State ◽  
Decision Making Processes ◽  
Fate Decision

Cell state transitions or cell fate decision making processes, such as cell development and cell pathological transformation, are believed to be determined by the regulatory network of genes, which intimately depend on the structures of chromosomes in the cell nucleus. The high temporal resolution picture of how chromosome reorganizes its 3D structure during the cell state transitions is the key to understanding the mechanisms of these fundamental cellular processes. However, this picture is still challenging to acquire at present. Here, we studied the chromosome structural dynamics during the cell state transitions among the pluripotent embryonic stem cell (ESC), the terminally differentiated normal cell and the cancer cell using landscape-switching model implemented in the molecular dynamics simulation. We considered up to 6 transitions, including differentiation, reprogramming, cancer formation and reversion. We found that the pathways can merge at certain stages during the transitions for the two processes having the same destination as the ESC or the normal cell. Before reaching the merging point, the two pathways are cell-type-specific. The chromosomes at the merging points show high structural similarity to the ones at the final cell states in terms of the contact maps, TADs and compartments. The post-merging processes correspond to the adaption of the chromosome global shape geometry through the chromosome compaction without significantly disrupting the contact formation. On the other hand, our detailed analysis showed no merging point for the two cancer formation processes initialized from the ESC and the normal cell, implying that cancer progression is a complex process and may be associated with multiple pathways. Our results draw a complete molecular picture of cell development and cancer at the dynamical chromosome structural level, and help our understanding of the molecular mechanisms of cell fate decision making processes.

scholarly journals The stem cell-specific protein TRIM71 inhibits maturation and activity of the pro-differentiation miRNA let-7 via two independent molecular mechanisms

2021 ◽  
Author(s):  
Lucia A. Torres-Fernández ◽  
Sibylle Mitschka ◽  
Thomas Ulas ◽  
Kilian Dahm ◽  
Matthias Becker ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Direct Interaction ◽  
Enrichment Analysis ◽  
Specific Protein ◽  
The One ◽  
Transcriptomic Changes

AbstractThe stem cell-specific RNA-binding protein TRIM71/LIN-41 was the first identified target of the pro-differentiation and tumor suppressor miRNA let-7. TRIM71 has essential functions in embryonic development and a proposed oncogenic role in several cancer types, such as hepatocellular carcinoma. Here, we show that TRIM71 regulates let-7 expression and activity via two independent mechanisms. On the one hand, TRIM71 enhances pre-let-7 degradation through its direct interaction with LIN28 and TUT4, thereby inhibiting let-7 maturation and indirectly promoting the stabilization of let-7 targets. On the other hand, TRIM71 represses the activity of mature let-7 via its RNA-dependent interaction with the RNA-Induced Silencing Complex (RISC) effector protein AGO2. We found that TRIM71 directly binds and stabilizes let-7 targets, suggesting that let-7 activity inhibition occurs on active RISCs. MiRNA enrichment analysis of several transcriptomic datasets from mouse embryonic stem cells and human hepatocellular carcinoma cells suggests that these let-7 regulatory mechanisms shape transcriptomic changes during developmental and oncogenic processes. Altogether, our work reveals a novel role for TRIM71 as a miRNA repressor and sheds light on the precise mechanistic dual regulation of let-7.

scholarly journals Oct-3/4 Maintains the Proliferative Embryonic Stem Cell State via Specific Binding to a Variant Octamer Sequence in the Regulatory Region of the UTF1 Locus

2005 ◽  
Vol 25 (12) ◽  
pp. 5084-5094 ◽  
Author(s):  
Masazumi Nishimoto ◽  
Satoru Miyagi ◽  
Toshiyuki Yamagishi ◽  
Takehisa Sakaguchi ◽  
Hitoshi Niwa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Specific Binding ◽  
Es Cells ◽  
Regulatory Region ◽  
Embryonic Stem ◽  
Cell State ◽  
Teratoma Formation ◽  
Stem Cell State

ABSTRACT The POU transcription factor Oct-3/4 has been shown to be critical for maintaining embryonic stem (ES) cell character. However, the molecular mechanisms underlying its function remain elusive. We have previously shown that among the POU transcription factor family of proteins, Oct-3/4 alone is able to bind to the regulatory region of the UTF1 gene bearing a variant octamer sequence together with Sox-2. Here, we demonstrate using Oct-3/4-Oct-6 chimeras that there is a precise correlation between the ability of proteins to form a complex on the UTF1 enhancer with Sox-2 and the ability to maintain the stem cell state in ES cells. Different chimeric proteins show differential abilities to form a Sox-2-containing complex on the UTF1 regulatory region, with a decrease in efficiency of the complex formation accompanied by a decrease in the level of UTF1 expression and the rate of cell proliferation. Overexpression of UTF1 in these slow-growing cells was able to restore their proliferation rate to wild-type levels. Moreover, UTF1 was also observed to have an effect on teratoma formation. These results suggest a molecular pathway by which Oct-3/4 induces rapid proliferation and tumorigenic properties of ES cells through activation of the UTF1 gene.

scholarly journals Dynamic Switching of Active Promoter and Enhancer Domains Regulates Tet1 and Tet2 Expression during Cell State Transitions between Pluripotency and Differentiation

2015 ◽  
Vol 35 (6) ◽  
pp. 1026-1042 ◽  
Author(s):  
Abhishek Sohni ◽  
Michela Bartoccetti ◽  
Rita Khoueiry ◽  
Lien Spans ◽  
Joris Vande Velde ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Cpg Island ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
State Transitions ◽  
Pluripotent Cells ◽  
Transcription Start Sites ◽  
Cell State ◽  
Regulatory Domains ◽  
Highly Active

The Tet 5-methylcytosine dioxygenases catalyze DNA demethylation by producing 5-hydroxymethylcytosine and further oxidized products. Tet1 and Tet2 are highly expressed in mouse pluripotent cells and downregulated to different extents in somatic cells, but the transcriptional mechanisms are unclear. Here we defined the promoter and enhancer domains in Tet1 and Tet2 . Within a 15-kb “superenhancer” of Tet1 , there are two transcription start sites (TSSs) with different activation patterns during development. A 6-kb promoter region upstream of the distal TSS is highly active in naive pluripotent cells, autonomously reports Tet1 expression in a transgenic system, and rapidly undergoes DNA methylation and silencing upon differentiation in cultured cells and native epiblast. A second TSS downstream, associated with a constitutively weak CpG-rich promoter, is activated by a neighboring enhancer in naive embryonic stem cells (ESCs) and primed epiblast-like cells (EpiLCs). Tet2 has a CpG island promoter with pluripotency-independent activity and an ESC-specific distal intragenic enhancer; the latter is rapidly downregulated in EpiLCs. Our study reveals distinct modes of transcriptional regulation at Tet1 and Tet2 during cell state transitions of early development. New transgenic reporters using Tet1 and Tet2 cis -regulatory domains may serve to distinguish nuanced changes in pluripotent states and the underlying epigenetic variations.

NOB1: A Potential Biomarker or Target in Cancer

2019 ◽  
Vol 20 (10) ◽  
pp. 1081-1089
Author(s):  
Weiwei Ke ◽  
Zaiming Lu ◽  
Xiangxuan Zhao
Keyword(s):  
Cancer Treatment ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Binding Protein ◽  
Tumor Development ◽  
Anticancer Therapy ◽  
Research Progress ◽  
Normal Tissues ◽  
Potential Biomarker

Human NIN1/RPN12 binding protein 1 homolog (NOB1), an RNA binding protein, is expressed ubiquitously in normal tissues such as the lung, liver, and spleen. Its core physiological function is to regulate protease activities and participate in maintaining RNA metabolism and stability. NOB1 is overexpressed in a variety of cancers, including pancreatic cancer, non-small cell lung cancer, ovarian cancer, prostate carcinoma, osteosarcoma, papillary thyroid carcinoma, colorectal cancer, and glioma. Although existing data indicate that NOB1 overexpression is associated with cancer growth, invasion, and poor prognosis, the molecular mechanisms behind these effects and its exact roles remain unclear. Several studies have confirmed that NOB1 is clinically relevant in different cancers, and further research at the molecular level will help evaluate the role of NOB1 in tumors. NOB1 has become an attractive target in anticancer therapy because it is overexpressed in many cancers and mediates different stages of tumor development. Elucidating the role of NOB1 in different signaling pathways as a potential cancer treatment will provide new ideas for existing cancer treatment methods. This review summarizes the research progress made into NOB1 in cancer in the past decade; this information provides valuable clues and theoretical guidance for future anticancer therapy by targeting NOB1.

The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

2019 ◽  
Vol 19 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Yuangang Wu ◽  
Xiaoxi Lu ◽  
Bin Shen ◽  
Yi Zeng
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Extracellular Matrix ◽  
Inflammatory Reaction ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

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