Long Non-Coding RNAs: A Novel Paradigm for Toxicology

Dempsey, Joseph L.; Cui, Julia Yue

doi:10.1093/toxsci/kfw203

Cited by 90 publications

(69 citation statements)

References 171 publications

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“…Emerging evidences and researches have demonstrated that the dysregulated expression of long noncoding RNAs (lncRNAs) play important roles in human cancers (Chandra Gupta & Nandan Tripathi, ). LncRNAs are type of non‐coding RNA transcribed from corresponding gene locus with more than 200 nucleotide length (Dempsey & Cui, ). LncRNAs epigenetically modulate biological functions of physiological and pathological activity via transcriptional and post‐transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA DANCR aggravates retinoblastoma through miR‐34c and miR‐613 by targeting MMP‐9

Wang

Yang

2018

Journal Cellular Physiology

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Long non-coding RNAs (lncRNAs) have been identified to play vital roles in cancers, including human retinoblastoma (RB). However, the deepgoing mechanism is still ambiguous. In present study, we investigate the biological role of lncRNA DANCR (differentiation antagonizing non-protein coding RNA) in carcinogenesis of RB. Results revealed that DANCR was up-regulated in RB tissue and cell lines. Moreover, the ectopic overexpression of DANCR indicated poor overall survivals and disease free survival (DFS) for RB patients. In vitro and in vivo experiments, DANCR knockdown suppress the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) correlated protein (N-cadherin, Vimentin) of RB cells. Bioinformatics analysis predicted that miR-34c and miR-613 targeted with 3'-UTR of DANCR, besides, miR-34c and miR-613 also targeted with 3'-UTR of MMP-9, which was validated by luciferase reporter assay. Functional experiments demonstrated that miR-34c and miR-613 could reverse the oncogenic function of DANCR in RB tumorigenesis. In conclusion, our results reveal that DANCR function as competing endogenous RNA (ceRNA) for miR-34c and miR-613 to modulate progression and metastasis in RB oncogenesis via targeting MMP-9, presenting the in-depth regulation of DANCR in RB and providing a novel insight for ceRNA mechanism for RB.

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Section: Introductionmentioning

confidence: 99%

Long noncoding RNA DANCR aggravates retinoblastoma through miR‐34c and miR‐613 by targeting MMP‐9

Wang

Yang

2018

Journal Cellular Physiology

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“…CAR ChIP-Seq experiments are challenging because of a lack of a good antibodytargeting endogenous CAR protein, although one could overcome this dmd.aspetjournals.org technical challenge using an adenovirus-based system to direct the expression of YFP-CAR fusion constructs in transgenic mice (Niu et al, 2018); however, it seems reasonable to speculate that a substantial number of differentially regulated intergenic lncRNAs by TCPOBOP may be a result of direct CAR-binding to the intergenic regions. Lastly, lncRNAs produced from the 39-UTR regions relative to PCGs may be important in protecting the mRNAs from miRNA-mediated degradation and/or inhibition of protein synthesis (Karapetyan et al, 2013;Dempsey and Cui, 2017). Although lncRNAs produced in distal regions may migrate to the 39-UTRs of PCGs and perform similar functions, the local production of lncRNAs may have a special advantage in this process.…”

Section: Discussionmentioning

confidence: 99%

“…According to the ENCODE Project, lncRNAs represent approximately 80% of functional sequences in the human DNA and are the predominant nonribosomal and nonmitochondrial RNA species in human cells (Kapranov et al, 2010;ENCODE Project Consortium, 2012). LncRNAs transcribed proximally or distally to protein-coding genes (PCGs) can modulate a wide spectrum of biologic events, including chromatin epigenetic remodeling, transcription factor assembly, alternative splicing, mRNA stability, and protein translation efficiency (Geisler and Coller, 2013;Karlsson and Baccarelli, 2016;Dempsey and Cui, 2017). Growing evidence in the literature suggests that lncRNAs are novel biomarkers and/or key contributors during physiologic, pharmacologic, and toxicologic responses, including complex human diseases, developmental disorders, as well as xenobioticinduced adverse outcomes (Dempsey and Cui, 2017).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Hepatic Long Noncoding RNAs by Pregnane X Receptor and Constitutive Androstane Receptor Agonists in Mouse Liver

Dempsey

Cui

2018

Drug Metab Dispos

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Altered expression of long noncoding RNAs (lncRNAs) by environmental chemicals modulates the expression of xenobiotic biotransformation-related genes and may serve as therapeutic targets and novel biomarkers of exposure. The pregnane X receptor (PXR/NR1I2) is a critical xenobiotic-sensing nuclear receptor that regulates the expression of many drug-processing genes, and it has similar target-gene profiles and DNA-binding motifs with another xenobiotic-sensing nuclear receptor, namely, constitutive andronstrane receptor (CAR/Nr1i3). To test our hypothesis that lncRNAs are regulated by PXR in concert with protein-coding genes (PCGs) and to compare the PXR-targeted lncRNAs with CAR-targeted lncRNAs, RNA-Seq was performed from livers of adult male C57BL/6 mice treated with corn oil, the PXR agonist PCN, or the CAR agonist 1, 4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPO-BOP). Among 125,680 known lncRNAs, 3843 were expressed in liver, and 193 were differentially regulated by PXR (among which 40% were also regulated by CAR). Most PXR-or CAR-regulated lncRNAs were mapped to the introns and 39-untranslated regions (UTRs) of PCGs, as well as intergenic regions. Combining the RNA-Seq data with a published PXR chromatin immunoprecipitation coupled with high-throughput sequencing; cytochrome P450 (P450; ChIP-Seq) data set, we identified 774 expressed lncRNAs with direct PXR-DNA binding sites, and 26.8% of differentially expressed lncRNAs had changes in PXR-DNA binding after PCN exposure. De novo motif analysis identified colocalization of PXR with liver receptor homolog (LRH-1), which regulates bile acid synthesis after PCN exposure. There was limited overlap of PXR binding with an epigenetic mark for transcriptional activation (histone-H3K4-di-methylation, H3K4me2) but no overlap with epigenetic marks for transcriptional silencing [H3 lysine 27 tri-methylation (H3K27me3) and DNA methylation]. Among differentially expressed lncRNAs, 264 were in proximity of PCGs, and the lncRNA-PCG pairs displayed a high coregulatory pattern by PXR and CAR activation. This study was among the first to demonstrate that lncRNAs are regulated by PXR and CAR activation and that they may be important regulators of PCGs involved in xenobiotic metabolism.

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“…Exposure to them is associated with the etiology of diseases. LncRNAs play critical roles in these processes (Dempsey & Cui, 2017;Karlsson & Baccarelli, 2016). The roles of lncRNAs in the toxicology of ECs receive great attention and are being investigated (Aigner et al, 2016).…”

Section: Roles Of Long Non-coding Rna In the Health Impact Of Envirmentioning

confidence: 99%

Emerging roles of long non‐coding RNAs in the toxicology of environmental chemicals

Huang

Liu

Dong

2018

J of Applied Toxicology

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Environmental chemicals (ECs) are drawing great attention to their effects on health and their toxicological mechanisms are being investigated. Long non-coding RNA (lncRNA) is a class of RNA with more than 200 nucleotides and does not have protein coding potential. Recently, it is emerging as a star molecule that participates in a wide range of physiological and pathological processes. It has been reported to be abnormally expressed in diseases. As an epigenetic factor, lncRNAs play an important role in the response of organisms to environmental stress. Their roles in the toxicity of ECs are being identified. Altered expression profiles of lncRNAs have been explored after exposure to ECs. Various kinds of ECs are reported to disturb the expression of lncRNAs in vitro and in vivo. Then, dysregulated lncRNAs can affect the expression of target genes directly or indirectly via regulating the level of microRNAs. The network among lncRNAs, microRNAs and mRNAs can initiate or impede specific signaling pathway and lead to adverse outcome upon exposure to ECs. Recovery of the lncRNAs level by overexpression or knockdown technology diminished the effect induced by ECs. In the review, biological roles of lncRNAs are depicted. The lncRNAs involved in the toxicology are summarized. Types of ECs that have been reported to affect the expression of lncRNAs are categorized. The interaction between various types of ECs and lncRNAs is discussed.

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Long Non-Coding RNAs: A Novel Paradigm for Toxicology

Cited by 90 publications

References 171 publications

Long noncoding RNA DANCR aggravates retinoblastoma through miR‐34c and miR‐613 by targeting MMP‐9

Long noncoding RNA DANCR aggravates retinoblastoma through miR‐34c and miR‐613 by targeting MMP‐9

Regulation of Hepatic Long Noncoding RNAs by Pregnane X Receptor and Constitutive Androstane Receptor Agonists in Mouse Liver

Emerging roles of long non‐coding RNAs in the toxicology of environmental chemicals

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