Origins and Function of VL30 lncRNA Packaging in Small Extracellular Vesicles: Implications for Cellular Physiology and Pathology

Long non-coding RNAs (lncRNAs) have emerged during the post-genomic era as significant epigenetic regulators. Viral-like 30 elements (VL30s) are a family of mouse retrotransposons that are transcribed into functional lncRNAs. Recent data suggest that VL30 RNAs are efficiently packaged in small extracellular vesicles (SEVs) through an SEV enrichment sequence. We analysed VL30 elements for the presence of the distinct 26 nt SEV enrichment motif and found that SEV enrichment is an inherent hallmark of the VL30 family, contained in 36 full-length elements, with a widespread chromosomal distribution. Among them, 25 elements represent active, present-day integrations and contain an abundance of regulatory sequences. Phylogenetic analysis revealed a recent spread of SEV-VL30s from 4.4 million years ago till today. Importantly, 39 elements contain an SFPQ-binding motif, associated with the transcriptional induction of oncogenes. Most SEV-VL30s reside in transcriptionally active regions, as characterised by their distribution adjacent to candidate cis-regulatory elements (cCREs). Network analysis of SEV-VL30-associated genes suggests a distinct transcriptional footprint associated with embryonal abnormalities and neoplasia. Given the established role of VL30s in oncogenesis, we conclude that their potential to spread through SEVs represents a novel mechanism for non-coding RNA biology with numerous implications for cellular homeostasis and disease.

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The Role of Extracellular Vesicles as Shuttles of RNA and Their Clinical Significance as Biomarkers in Hepatocellular Carcinoma

Genes ◽

10.3390/genes12060902 ◽

2021 ◽

Vol 12 (6) ◽

pp. 902

Author(s):

Eva Costanzi ◽

Carolina Simioni ◽

Gabriele Varano ◽

Cinzia Brenna ◽

Ilaria Conti ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Extracellular Vesicles ◽

Tumor Metastasis ◽

Biological Processes ◽

Rna Molecules ◽

Expression Of Genes ◽

Non Coding Rna ◽

Donor Cells ◽

Relevant Role

Extracellular vesicles (EVs) have attracted interest as mediators of intercellular communication following the discovery that EVs contain RNA molecules, including non-coding RNA (ncRNA). Growing evidence for the enrichment of peculiar RNA species in specific EV subtypes has been demonstrated. ncRNAs, transferred from donor cells to recipient cells, confer to EVs the feature to regulate the expression of genes involved in differentiation, proliferation, apoptosis, and other biological processes. These multiple actions require accuracy in the isolation of RNA content from EVs and the methodologies used play a relevant role. In liver, EVs play a crucial role in regulating cell–cell communications and several pathophysiological events in the heterogeneous liver class of cells via horizontal transfer of their cargo. This review aims to discuss the rising role of EVs and their ncRNAs content in regulating specific aspects of hepatocellular carcinoma development, including tumorigenesis, angiogenesis, and tumor metastasis. We analyze the progress in EV-ncRNAs’ potential clinical applications as important diagnostic and prognostic biomarkers for liver conditions.

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Epigenomic Analysis of RAD51 ChIP-seq Data Reveals cis-regulatory Elements Associated with Autophagy in Cancer Cell Lines

Cancers ◽

10.3390/cancers13112547 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2547

Author(s):

Keunsoo Kang ◽

Yoonjung Choi ◽

Hyeonjin Moon ◽

Chaelin You ◽

Minjin Seo ◽

...

Keyword(s):

Gene Regulation ◽

Homologous Recombination ◽

Cell Lines ◽

Regulatory Elements ◽

Binding Motif ◽

Genome Wide ◽

E Box ◽

Autophagy Pathway ◽

Mcf 7

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51-bound cis-regulatory elements in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-associated cis-regulatory elements in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway, such as ATG3 and ATG5, were significantly occupied by RAD51 and regulated by RAD51 in HepG2 and MCF-7 cell lines. Taken together, these results unveiled a novel role of RAD51 and provided evidence that RAD51-associated cis-regulatory elements could possibly be involved in regulating autophagy-related genes with E-box binding proteins.

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A Genome-Wide Analysis of Pathogenesis-Related Protein-1 (PR-1) Genes from Piper nigrum Reveals Its Critical Role during Phytophthora capsici Infection

Genes ◽

10.3390/genes12071007 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1007

Author(s):

Divya Kattupalli ◽

Asha Sreenivasan ◽

Eppurathu Vasudevan Soniya

Keyword(s):

Phytophthora Capsici ◽

Regulatory Elements ◽

Piper Nigrum ◽

Binding Motif ◽

Altered Expression ◽

Genome Wide ◽

A Genome ◽

Pathogenesis Related Protein ◽

Pathogenesis Related

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic and abiotic stresses, plants employ a broad array of mechanisms that includes the accumulation of pathogenesis-related (PR) proteins. Through a genome-wide survey, eleven PR-1 genes that belong to a CAP superfamily protein with a caveolin-binding motif (CBM) and a CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR-1 homologs differ in their signal peptide motifs and core amino acid composition in the functional protein domains. The conserved motifs of PnPR-1 proteins were identified using MEME. Most of the PnPR-1 proteins were basic in nature. Secondary and 3D structure analyses of the PnPR-1 proteins were also predicted, which may be linked to a functional role in P. nigrum. The GO and KEGG functional annotations predicted their function in the defense responses of plant-pathogen interactions. Furthermore, a transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to the P. nigrum-P. capsici interaction pathway. An altered expression pattern was detected for PnPR-1 transcripts among which a significant upregulation was noted for basic PnPR-1 genes such as CL10113.C1 and Unigene17664. The drastic variation in the transcript levels of CL10113.C1 was further validated through qRT-PCR and it showed a significant upregulation in infected leaf samples compared with the control. A subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes. This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum-P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards a P. capsici infection in Panniyur-1 plants.

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Extracellular Vesicles and Thrombosis: Update on the Clinical and Experimental Evidence

International Journal of Molecular Sciences ◽

10.3390/ijms22179317 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9317

Author(s):

Konstantinos Zifkos ◽

Christophe Dubois ◽

Katrin Schäfer

Keyword(s):

Experimental Evidence ◽

Extracellular Vesicles ◽

Thrombus Formation ◽

Experimental Studies ◽

Cell Types ◽

Heterogenous Group ◽

Clearance Mechanism ◽

And Function ◽

Role And Function

Extracellular vesicles (EVs) compose a heterogenous group of membrane-derived particles, including exosomes, microvesicles and apoptotic bodies, which are released into the extracellular environment in response to proinflammatory or proapoptotic stimuli. From earlier studies suggesting that EV shedding constitutes a cellular clearance mechanism, it has become evident that EV formation, secretion and uptake represent important mechanisms of intercellular communication and exchange of a wide variety of molecules, with relevance in both physiological and pathological situations. The putative role of EVs in hemostasis and thrombosis is supported by clinical and experimental studies unraveling how these cell-derived structures affect clot formation (and resolution). From those studies, it has become clear that the prothrombotic effects of EVs are not restricted to the exposure of tissue factor (TF) and phosphatidylserines (PS), but also involve multiplication of procoagulant surfaces, cross-linking of different cellular players at the site of injury and transfer of activation signals to other cell types. Here, we summarize the existing and novel clinical and experimental evidence on the role and function of EVs during arterial and venous thrombus formation and how they may be used as biomarkers as well as therapeutic vectors.

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Genome-Wide Analysis of PR-1 Genes From Piper Nigrum Reveals Critical Role in Defense Response During Phytophthora Capsici Infection

10.21203/rs.3.rs-130603/v1 ◽

2020 ◽

Author(s):

Divya Kattupalli ◽

Asha Sriniva ◽

Soniya E V

Keyword(s):

Function Analysis ◽

Phytophthora Capsici ◽

Critical Role ◽

Defense Responses ◽

Regulatory Elements ◽

Black Pepper ◽

Piper Nigrum ◽

Binding Motif ◽

Genome Wide

Abstract Background: Black pepper is a prominent spice which is an indispensable ingredient in culinary and traditional medicine. Phytophthora capsici, the causative agent of foot rot disease causes drastic constraint in black pepper cultivation and productivity. To counterattack various biotic and abiotic stresses plants employ a broad array of mechanisms one such includes the accumulation of pathogenesis-related (PR) proteins. Several studies have reported the role of PR-1 proteins in triggering the plant defenses during plant-oomycete interaction.Results: Through the genome-wide survey, eleven PR-1 genes that belongs to a CAP superfamily protein with Caveolin-Binding Motif (CBM) and CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR1 homologs differ in their signal peptide motifs, and core amino acid sequence composition in the functional protein domains. The GO, biological function analysis reveals their role in defense responses and response to biotic stimulus whereas the KEGG functional annotation predicted their function in the plant-pathogen interactions. Furthermore, transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to P. nigrum - P. capsici interaction pathway. The differentially expressed pathogen-responsive PR-1 gene was validated through qRT-PCR. Subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes.Conclusion: This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum - P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards P. capsici infection in Panniyur-1 plants.

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Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms21041377 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1377

Author(s):

Pavan Kumar Dhanyamraju ◽

Soumya Iyer ◽

Gayle Smink ◽

Yevgeniya Bamme ◽

Preeti Bhadauria ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tumor Suppressor ◽

Chromatin Remodeling ◽

Target Genes ◽

Cellular Proliferation ◽

Lymphoblastic Leukemia ◽

Regulatory Elements ◽

Binding Motif ◽

Functional Inactivation

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

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Structure and function of an ectopic Polycomb chromatin domain

Science Advances ◽

10.1126/sciadv.aau9739 ◽

2019 ◽

Vol 5 (1) ◽

pp. eaau9739 ◽

Cited By ~ 6

Author(s):

Sandip De ◽

Yuzhong Cheng ◽

Ming-an Sun ◽

Natalie D. Gehred ◽

Judith A. Kassis

Keyword(s):

Domain Structure ◽

Regulatory Elements ◽

Structure And Function ◽

Polycomb Group ◽

Chromatin Domain ◽

Repressive Mark ◽

Group Response ◽

Dna Elements ◽

And Function

Polycomb group proteins (PcGs) drive target gene repression and form large chromatin domains. InDrosophila, DNA elements known as Polycomb group response elements (PREs) recruit PcGs to the DNA. We have shown that, within theinvected-engrailed(inv-en) Polycomb domain, strong, constitutive PREs are dispensable for Polycomb domain structure and function. We suggest that the endogenous chromosomal location imparts stability to this Polycomb domain. To test this possibility, a 79-kbentransgene was inserted into other chromosomal locations. This transgene is functional and forms a Polycomb domain. The spreading of the H3K27me3 repressive mark, characteristic of PcG domains, varies depending on the chromatin context of the transgene. Unlike at the endogenous locus, deletion of the strong, constitutive PREs from the transgene leads to both loss- and gain-of function phenotypes, demonstrating the important role of these regulatory elements. Our data show that chromatin context plays an important role in Polycomb domain structure and function.

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The Emerging Role of Long Non-Coding RNAs in Plant Defense Against Fungal Stress

International Journal of Molecular Sciences ◽

10.3390/ijms21082659 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2659

Author(s):

Hong Zhang ◽

Huan Guo ◽

Weiguo Hu ◽

Wanquan Ji

Keyword(s):

Stress Responses ◽

Higher Plants ◽

Regulatory Elements ◽

Cellular Functions ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Resistance To Infection ◽

Regulatory Functions ◽

Long Non Coding Rna

Growing interest and recent evidence have identified long non-coding RNA (lncRNA) as the potential regulatory elements for eukaryotes. LncRNAs can activate various transcriptional and post-transcriptional events that impact cellular functions though multiple regulatory functions. Recently, a large number of lncRNAs have also been identified in higher plants, and an understanding of their functional role in plant resistance to infection is just emerging. Here, we focus on their identification in crop plant, and discuss their potential regulatory functions and lncRNA-miRNA-mRNA network in plant pathogen stress responses, referring to possible examples in a model plant. The knowledge gained from a deeper understanding of this colossal special group of plant lncRNAs will help in the biotechnological improvement of crops.

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The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications

Cells ◽

10.3390/cells7080093 ◽

2018 ◽

Vol 7 (8) ◽

pp. 93 ◽

Cited By ~ 28

Author(s):

James Jabalee ◽

Rebecca Towle ◽

Cathie Garnis

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Tumor Stroma ◽

Therapeutic Implications ◽

Membrane Bound ◽

Immune Destruction ◽

And Function ◽

Cargo Molecule

Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound structures that play key roles in intercellular communication. EVs are potent regulators of tumorigenesis and function largely via the shuttling of cargo molecules (RNA, DNA, protein, etc.) among cancer cells and the cells of the tumor stroma. EV-based crosstalk can promote proliferation, shape the tumor microenvironment, enhance metastasis, and allow tumor cells to evade immune destruction. In many cases these functions have been linked to the presence of specific cargo molecules. Herein we will review various types of EV cargo molecule and their functional impacts in the context of oncology.

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Signal and noise in circRNA translation

10.1101/2020.12.10.418848 ◽

2020 ◽

Author(s):

TB Hansen

Keyword(s):

Data Analysis ◽

Protein Production ◽

Circular Rnas ◽

Non Coding Rna ◽

Rna Biology ◽

And Function

AbstractWithin recent years, circular RNAs (circRNAs) have been an attractive new field of research in RNA biology and disease. Consequently, numerous studies have been published towards the disclosure of circRNA biogenesis and function. Initially, circRNAs were described as a subclass of cytoplasmic non-coding RNA, however, a few recent observations have proposed that circRNAs may instead be templates for protein production. The extent to which this is the case is currently debated, and therefore using rigorous data analysis and proper experimental setups is instrumental to settle the current controversies. Here, the conventional experiments used for detecting circRNA translation are outlined, and guidelines to distinguish signal from the inherent noise are discussed. While these guidelines are specific for circRNA translation, most also apply to all other aspects of non-canonical translation.

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