scholarly journals The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs

2021 ◽  
Vol 118 (31) ◽  
pp. e2025539118
Author(s):  
Ephrath Tesfaye ◽  
Elena Martinez-Terroba ◽  
Jordan Bendor ◽  
Lauren Winkler ◽  
Christiane Olivero ◽  
...  
Keyword(s):  
Target Genes ◽  
Noncoding Rnas ◽  
Transcriptional Response ◽  
Long Noncoding Rnas ◽  
Tumor Type ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Suppressor Mechanism ◽  
Functional Investigation ◽  
Tumor Types

The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest.

Abstract 91: Genome-wide Identification and Characterization of Cardiac Hypertrophy-related Long Noncoding RNAs in Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhanpeng Huang ◽  
Gengze Wu ◽  
Jian-Hua Yang ◽  
Jian Ding ◽  
Jinghai Chen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Target Genes ◽  
Troponin T ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Functional Screening ◽  
Loss Of Function ◽  
Specific Expression ◽  
Functional Conservation ◽  
Virus Serotype

Long noncoding RNAs (LncRNAs) are RNA transcripts longer than 200 nucleotides that lack protein-coding potential. Although thousands of lncRNAs have been identified, only a few have been linked to cardiac gene expression and function. In this study, we identified, from genome-scale RNA-seq data, 12 candidate lncRNAs associated with cardiac hypertrophy (CH-lncRNAs). The expression of these lncRNAs was altered in mouse models of cardiac hypertrophy induced by transverse aortic constriction (TAC)- or CnA transgene. To determine the function of these lncRNAs, we developed an adeno-associated virus serotype 9 (AAV9)-based functional screening in postnatal mice. An AAV9:cTNT vector, in which the cardiac troponin T (cTNT) promoter was used to direct cardiac-specific expression of target genes, was utilized to overexpress or knockdown candidate lncRNAs in mouse hearts. Postnatal day 1 wild type or CnA transgenic pups were injected with AAV9 viruses and cardiac function was measured one and two months later. Thus far, we have tested 15 candidate lncRNAs for both gain- and loss-of-function studies. Among them, two lncRNAs were demonstrated regulating hypertrophy growth when knocked down. Finally, we identified the human homologues of CH-lncRNA through analyzing the conservation of the promoter regions of lncRNA genes. We showed that the expression of these human CH-lncRNA was dysregulated in human diseased hearts, suggesting the functional conservation of these lncRNAs in cardiac disease. Our study therefore demonstrated that lncRNAs are important regulator of cardiac hypertrophy and disease.

scholarly journals The Roles of Long Noncoding RNAs HNF1α-AS1 and HNF4α-AS1 in Drug Metabolism and Human Diseases

2020 ◽  
Vol 6 (2) ◽  
pp. 24 ◽  
Author(s):  
Liming Chen ◽  
Yifan Bao ◽  
Suzhen Jiang ◽  
Xiao-bo Zhong
Keyword(s):  
Drug Metabolism ◽  
Drug Toxicity ◽  
Target Genes ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Future Directions ◽  
Protein Coding ◽  
Mirna Sponge ◽  
Current Review ◽  
And Function

Long noncoding RNAs (lncRNAs) are RNAs with a length of over 200 nucleotides that do not have protein-coding abilities. Recent studies suggest that lncRNAs are highly involved in physiological functions and diseases. lncRNAs HNF1α-AS1 and HNF4α-AS1 are transcripts of lncRNA genes HNF1α-AS1 and HNF4α-AS1, which are antisense lncRNA genes located in the neighborhood regions of the transcription factor (TF) genes HNF1α and HNF4α, respectively. HNF1α-AS1 and HNF4α-AS1 have been reported to be involved in several important functions in human physiological activities and diseases. In the liver, HNF1α-AS1 and HNF4α-AS1 regulate the expression and function of several drug-metabolizing cytochrome P450 (P450) enzymes, which also further impact P450-mediated drug metabolism and drug toxicity. In addition, HNF1α-AS1 and HNF4α-AS1 also play important roles in the tumorigenesis, progression, invasion, and treatment outcome of several cancers. Through interacting with different molecules, including miRNAs and proteins, HNF1α-AS1 and HNF4α-AS1 can regulate their target genes in several different mechanisms including miRNA sponge, decoy, or scaffold. The purpose of the current review is to summarize the identified functions and mechanisms of HNF1α-AS1 and HNF4α-AS1 and to discuss the future directions of research of these two lncRNAs.

scholarly journals Transcriptional profiling of long noncoding RNAs associated with leaf-color mutation in Ginkgo biloba L

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yaqiong Wu ◽  
Jing Guo ◽  
Tongli Wang ◽  
Fuliang Cao ◽  
Guibin Wang
Keyword(s):  
Ginkgo Biloba ◽  
High Throughput Sequencing ◽  
Target Genes ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Differentially Expressed ◽  
Biological Processes ◽  
Leaf Color ◽  
Wide Range ◽  
Color Mutation

Abstract Background Long noncoding RNAs (lncRNAs) play an important role in diverse biological processes and have been widely studied in recent years. However, the roles of lncRNAs in leaf pigment formation in ginkgo (Ginkgo biloba L.) remain poorly understood. Results In this study, lncRNA libraries for mutant yellow-leaf and normal green-leaf ginkgo trees were constructed via high-throughput sequencing. A total of 2044 lncRNAs were obtained with an average length of 702 nt and typically harbored 2 exons. We identified 238 differentially expressed lncRNAs (DELs), 32 DELs and 49 differentially expressed mRNAs (DEGs) that constituted coexpression networks. We also found that 48 cis-acting DELs regulated 72 target genes, and 31 trans-acting DELs regulated 31 different target genes, which provides a new perspective for the regulation of the leaf-color mutation. Due to the crucial regulatory roles of lncRNAs in a wide range of biological processes, we conducted in-depth studies on the DELs and their targets and found that the chloroplast thylakoid membrane subcategory and the photosynthesis pathways (ko00195) were most enriched, suggesting their potential roles in leaf coloration mechanisms. In addition, our correlation analysis indicates that eight DELs and 68 transcription factors (TFs) might be involved in interaction networks. Conclusions This study has enriched the knowledge concerning lncRNAs and provides new insights into the function of lncRNAs in leaf-color mutations, which will benefit future selective breeding of ginkgo.

scholarly journals Bioinformatic Analysis Identified Potentially Prognostic Long Noncoding RNAs and MicroRNAs for Gastric Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jiao Guo ◽  
Yongda Liu ◽  
Ping Zhao
Keyword(s):  
Gastric Cancer ◽  
Clinical Data ◽  
Target Genes ◽  
Univariate Analysis ◽  
Noncoding Rnas ◽  
Clinical Information ◽  
Bioinformatic Analysis ◽  
Long Noncoding Rnas ◽  
Prognostic Indicators ◽  
Cox Analysis

Gastric cancer (GC) is the fifth most common malignant tumor in the world. The present study was performed to discover the potential diagnostic and therapeutic long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) of GC. Data used in this study to identify differentially expressed lncRNAs (DElncRNAs) and miRNAs (DEmiRNAs) were obtained from 187 GC tissues and 32 adjacent nontumor tissues. The total clinical data on GC included 187 cases. The above data were from the TCGA database. RStudio/Bioconductor software was used to conduct univariate analysis, the least absolute shrinkage and selection operator (LASSO) Cox, and multivariate Cox proportional risk regression for the DElncRNAs and DEmiRNAs. Clinical information was analyzed through univariate and multivariate Cox analysis. Results: five lncRNAs (AC007785.3, AC079385.3, LINC00392, LINC01729, and U95743.1) and two miRNAs (hsa-miR-3174, hsa-miR-605) were proven to be independent prognostic indicators of GC. Results of the Kaplan-Meier survival analysis showed that AC007785.3, AC079385.3, LINC01729, miR-3174, and miR-605 were significantly correlated with OS of GC. The target genes of AC079385.3, miR-3174, and miR-605 were obtained and clustered mainly on MAPK and cGMP-PKG signaling pathways. The clinical data showed that age and clinicopathologic stage were correlated with the prognosis of GC. Furthermore, AC007785.3 was associated with metastasis of GC, and miR-3174 was associated with the primary tumor condition of GC. We identified three lncRNAs (AC007785.3, AC079385.3, LINC01729), two miRNAs (miR-3174, miR-605), and clinical factors related to the pathogenesis and prognosis of GC. Our predicted results provide a possible entry point for the study of prognostic markers for GC.

scholarly journals The Significance of Heat Responsive Long Noncoding RNAs in Rice Discovered by Integrating Expression, Network and Genetic Analyses

2021 ◽  
Author(s):  
zhengfeng zhang ◽  
Huahua Zhong ◽  
Bo Nan ◽  
Benze Xiao
Keyword(s):  
Heat Stress ◽  
Steady State ◽  
Target Genes ◽  
Expression Profiles ◽  
Noncoding Rnas ◽  
Interaction Network ◽  
Long Noncoding Rnas ◽  
Plant Responses ◽  
Sequence Motif ◽  
Motif Analysis

Abstract Long noncoding RNAs (lncRNAs) play vital roles in plant responses to environments. However, the systematic identification of lncRNAs in rice under heat stress remains to be fully performed. We performed steady-state strand-specific RNA-seq for rice seedlings under heat stress to predict lncRNAs. In total, 2743 lncRNAs were predicted, and their expression profiles in response to heat treatments were provided. We identified 231 differentially expressed lncRNAs (DELs) in their steady-state level under heat stress, including 31 DELs common to both varieties and 103 and 97 specific to ZS97B and SYD2, respectively, all defined as heat-responsive lncRNAs (HRLs). The target-coding genes of HRLs were predicted through cis-action, ceRNAs, precursors of miRNA, antisense modes and other trans-action targets. GO and KEGG enrichment analyses of HRL targets revealed functions in which HRLs were involved. The interaction network between HRLs, target genes and relevant miRNAs was constructed. The HRLs and their targets were integrated with publicly available QTLs for rice seedling growth under heat stimulus, and 10 HRLs and 12 target genes were co-localized with 5 heat-relevant QTLs. Sequence motif analysis found a few significant motifs enriched in 231 HRL sequences, and the differential significance of enriched motifs between HRLs and background sequences was tested. Our findings provide new insights into the characterization of lncRNAs in terms of the heat response and resources for further investigations of plant heat tolerance improvement.

scholarly journals Global Transcriptome Analysis of Long Noncoding RNAs in Rice Seed Development

2021 ◽  
Vol 25 (04) ◽  
pp. 777-785
Author(s):  
Jingai Tan
Keyword(s):  
Seed Development ◽  
Target Genes ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Differentially Expressed ◽  
High Yield ◽  
Rice Seed ◽  
Extracellular Region ◽  
Dynamic Expression ◽  
Three Stages

Rice seed development involves an intricate regulatory network that directly determines seed size and weight. Long noncoding RNAs (lncRNAs) have been defined as key regulators of gene expression involved in diverse biological processes. However, the function of lncRNAs in rice seed development is still poorly understood. We performed paired-end RNA sequencing of Nipponbare rice at 5, 10 and 15 DPA (days post anthesis) in two different environments (early and middle-season rice). A total of 382 lncRNAs were detected as differentially expressed among these stages, including 344 and 307 lncRNAs in early and middle-season rice, respectively, and 70.42% (269 of 382) of the lncRNAs were found in both environments. The results showed that environment had little effect on the expression of lncRNAs. Furthermore, there were 127, 172, and 31 DElncs (differentially expressed lncRNAs) and 154, 140, and 59 DElncs in early and middle-season rice, respectively, in comparisons of 10_DPA vs 5_DPA, 15_DPA vs 5_DPA and 15_DPA vs 10_DPA. This result indicated that the number and expression level of lncRNAs at 5 DAP were significantly different from those at 10 DAP and 15 DAP. Furthermore, GO pathway analysis of cis target genes of DElncs in 10_DPA vs 5_DPA and 15_DPA vs 5_DPA revealed that the significant GO pathways were extracellular region, nutrient reservoir activity and cell wall macromolecule catabolic process. Our study revealed dynamic expression of lncRNAs in three stages and systematically explored the differences in lncRNAs between early and middle-season rice, which could provide a valuable resource for future high-yield breeding. © 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers © 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers© 2021 Friends Science Publishers©

scholarly journals Genome-wide discovery and characterization of long noncoding RNAs in African oil palm (Elaeis guineensis Jacq.)

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9585
Author(s):  
Wei Xia ◽  
Yajing Dou ◽  
Rui Liu ◽  
Shufang Gong ◽  
Dongyi Huang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Oil Palm ◽  
Target Genes ◽  
De Novo ◽  
Elaeis Guineensis ◽  
Expression Patterns ◽  
Noncoding Rnas ◽  
Snp Markers ◽  
Long Noncoding Rnas ◽  
Rna Seq

Long noncoding RNAs (lncRNAs) are an important class of genes and play important roles in a range of biological processes. However, few reports have described the identification of lncRNAs in oil palm. In this study, we applied strand specific RNA-seq with rRNA removal to identify 1,363 lncRNAs from the equally mixed tissues of oil palm spear leaf and six different developmental stages of mesocarp (8–24 weeks). Based on strand specific RNA-seq data and 18 released oil palm transcriptomes, we systematically characterized the expression patterns of lncRNA loci and their target genes. A total of 875 uniq target genes for natural antisense lncRNAs (NAT-lncRNA, 712), long intergenic noncoding RNAs (lincRNAs, 92), intronic-lncRNAs (33), and sense-lncRNAs (52) were predicted. A majority of lncRNA loci (77.8%–89.6%) had low expression in 18 transcriptomes, while only 89 lncRNA loci had medium to high expression in at least one transcriptome. Coexpression analysis between lncRNAs and their target genes indicated that 6% of lncRNAs had expression patterns positively correlated with those of target genes. Based on single nucleotide polymorphism (SNP) markers derived from our previous research, 6,882 SNPs were detected for lncRNAs and 28 SNPs belonging to 21 lncRNAs were associated with the variation of fatty acid contents. Moreover, seven lncRNAs showed expression patterns positively correlated expression pattern with those of genes in de novo fatty acid synthesis pathways. Our study identified a collection of lncRNAs for oil palm and provided clues for further research into lncRNAs that may regulate mesocarp development and lipid metabolism.

scholarly journals Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emily L. Flam ◽  
Ludmila Danilova ◽  
Dylan Z. Kelley ◽  
Elena Stavrovskaya ◽  
Theresa Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Target Genes ◽  
Human Cancer ◽  
Genetic Alterations ◽  
Tumor Type ◽  
Gene Pairs ◽  
Aberrant Gene Expression ◽  
Tumor Types ◽  
Aberrant Gene

Abstract Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV + OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV + OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV + OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV + OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.

scholarly journals Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway

2016 ◽  
Vol 12 (6) ◽  
pp. 4605-4612 ◽  
Author(s):  
Ping Wang ◽  
Jiayue Cui ◽  
Jihong Wen ◽  
Yunhui Guo ◽  
Liangzi Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Hepg2 Cell ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
P53 Signaling ◽  
Cycle Arrest ◽  
P53 Signaling Pathway

scholarly journals Systematic identification and characterization of Aedes aegypti long noncoding RNAs

2018 ◽  
Author(s):  
Azali Azlan ◽  
Sattam M. Obeidat ◽  
Muhammad Amir Yunus ◽  
Ghows Azzam
Keyword(s):  
Aedes Aegypti ◽  
Early Stage ◽  
Developmental Regulation ◽  
Noncoding Rnas ◽  
Gc Content ◽  
Transcriptional Response ◽  
Long Noncoding Rnas ◽  
Blood Sucking ◽  
Virus Serotype ◽  
Systematic Identification

Long noncoding RNAs (lncRNAs) play diverse roles in biological process including developmental regulation and host-pathogen interactions. Aedes aegypti (Ae. aegypti), a blood-sucking mosquito, is the principal vector responsible for replication and transmission of arboviruses including dengue, zika, and chikungunya virus. Systematic identification and developmental characterisation of Ae. aegypti lncRNAs are still limited. We performed genome-wide identification of lncRNAs followed by developmental profiling of lncRNA expression in Ae. aegypti. We identified a total of 4,689 novel lncRNA transcripts, of which 2,064, 2,076, and 549 were intergenic, intronic, and antisense respectively. Ae. aegypti lncRNAs shared many of the characteristics with other species including low expression, low GC content, short in length, low conservation, and their expression tended to be correlated with neighbouring and antisense protein-coding genes. Subsets of lncRNAs showed evidence that they were maternally inherited, suggesting potential roles in early-stage embryos. Additionally, lncRNAs showed higher tendency to be expressed in developmental and temporal specific manner. Upon infection of Ae. aegypti cells with dengue virus serotype 1, we identified 2,335 differentially expressed transcripts, 957 of which were lncRNA transcripts. The systematic annotation, developmental profiling, and transcriptional response upon virus infection provide foundation for future investigation on the function of Ae. aegypti lncRNAs.

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