Down-regulation of long noncoding RNA HOXA11-AS nullifies the impact of microRNA-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis.

OBJECTIVES: This study was directed towards exploring the impacts of lncRNA HOXA11-AS-mediated microRNA (miR)-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis (OA). METHODS: The articular cartilages were provided by OA patients who received total knee arthroplasty, and Human Chondrocyte (HC)-OA (HCOA) was also attained. The miR-506-3p and HOXA11-AS expressions in articular cartilages from OA patients and HCOA cells were analyzed via qPCR. After gain- and loss-of-function assays in HCOA cells, MTT assay and flow cytometry (FC) were used for assessing cell viability and apoptosis, accordingly. The levels of PIK3CA, AKT, and mTOR as well as AKT and mTOR phosphorylation levels assessed using western blotting (WB). The targeting correlation of HOXA11-AS and miR-506-3p as well as miR-506-3p and PIK3CA was assessed through Dual-Luciferase Reporter gene Assay (DLRA). RESULT: The articular cartilages from OA patients and Human Chondrocyte (HC)-OA (HCOA) cells showed increased HOXA11-AS and decreased miR-506-3p. Mechanistically, HOXA11-AS was capable of binding to miR-506-3p to increase PIK3CA, the target gene of miR-506-3p. miR-506-3p suppression facilitated HCOA cell proliferation and reduced their apoptosis, which was nullified by further silencing HOXA11-AS or silencing PIK3CA. The down-regulation of HOXA11-AS disrupted the PI3K/AKT/mTOR pathway, which was counteracted by further miR-506-3p inhibition. CONCLUSION: The silencing of HOXA11-AS might block the PI3K/AKT/mTOR pathway through miR-506-3p up-regulation, thereby restricting HCOA cell proliferation and provoking apoptosis.

Down-regulation of long noncoding RNA HOXA11-AS nullifies the impact of microRNA-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis

Abstract Objectives This study was directed towards exploring the impacts of lncRNA HOXA11-AS-mediated microRNA (miR)-506-3p on chondrocytes proliferation and apoptosis in osteoarthritis (OA). Methods The articular cartilages were provided by OA patients who received total knee arthroplasty, and Human Chondrocyte (HC)-OA (HC-OA) was also attained. The miR-506-3p and HOXA11-AS expressions in articular cartilages from OA patients and HC-OA cells were analyzed via qPCR. After gain- and loss-of-function assays in HC-OA cells, MTT assay and flow cytometry (FC) were used for assessing cell viability and apoptosis, accordingly. The levels of PIK3CA, AKT, and mTOR as well as AKT and mTOR phosphorylation levels assessed using western blotting (WB). The targeting correlation of HOXA11-AS and miR-506-3p as well as miR-506-3p and PIK3CA was assessed through Dual-Luciferase Reporter gene Assay (DLRA). Result The articular cartilages from OA patients and Human Chondrocyte (HC)-OA (HC-OA) cells showed increased HOXA11-AS and decreased miR-506-3p. Mechanistically, HOXA11-AS was capable of binding to miR-506-3p to increase PIK3CA, the target gene of miR-506-3p. miR-506-3p suppression facilitated HC-OA cell proliferation and reduced their apoptosis, which was nullified by further silencing HOXA11-AS or silencing PIK3CA. The down-regulation of HOXA11-AS disrupted the PI3K/AKT/mTOR pathway, which was counteracted by further miR-506-3p inhibition. Conclusion The silencing of HOXA11-AS might block the PI3K/AKT/mTOR pathway through miR-506-3p up-regulation, thereby restricting HC-OA cell proliferation and provoking apoptosis.

Long noncoding RNA-mediated epigenetic regulation of auxin-related genes controls shade avoidance syndrome in Arabidopsis.

The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA-DNA hybrids (R-loops) and modulating local three-dimensional chromatin conformation. Here, we show that APOLO regulates shade avoidance syndrome by dynamically modulating expression of key factors. In response to far-red (FR) light, expression of APOLO anti-correlates with that of its target BRANCHED1 (BRC1), a master regulator of shoot branching in Arabidopsis thaliana. APOLO deregulation results in BRC1 transcriptional repression and an increase in the number of branches. Accumulation of APOLO transcription fine-tunes the formation of a repressive chromatin loop encompassing the BRC1 promoter, which normally occurs only in leaves and in a late response to far-red light treatment in axillary buds. In addition, our data reveal that APOLO participates in leaf hyponasty, in agreement with its previously reported role in the control of auxin homeostasis through direct modulation of auxin synthesis gene YUCCA2, and auxin efflux genes PID and WAG2. We show that direct application of APOLO RNA to leaves results in a rapid increase in auxin signaling that is associated with changes in the plant response to far-red light. Collectively, our data support the view that lncRNAs coordinate shade avoidance syndrome in A. thaliana, and reveal their potential as exogenous bioactive molecules. Deploying exogenous RNAs that modulate plant-environment interactions may therefore become a new tool for sustainable agriculture.

Construction and analysis of the tapping panel dryness-related lncRNA/circRNA-miRNA-mRNA ceRNA network in latex of Hevea brasiliensis.

Tapping panel dryness (TPD) results in a severe reduction in latex yield in Hevea brasiliensis. However, the molecular regulatory mechanisms of TPD occurrence are still largely unclear. In this study, whole-transcriptome sequencing was carried out on latex from TPD and healthy trees. In total, 7078 long noncoding RNAs (lncRNAs), 3077 circular RNAs (circRNAs), 4956 miRNAs, and 25041 mRNAs were identified in latex, among which 435 lncRNAs, 68 circRNAs, 320 miRNAs, and 1574 mRNAs were differentially expressed in the latex of TPD trees. GO and KEGG analyses indicated that plant hormone signal transduction, MAPK signaling pathway, and ubiquitin-mediated proteolysis were the key pathways associated with TPD onset. Phytohormone profiling revealed significant changes in the contents of 28 hormonal compounds, among which ACC, ABA, IAA, GA, and JA contents were increased, while SA content was reduced in TPD latex, suggesting that hormone homeostasis is disrupted in TPD trees. Furthermore, we constructed a TPD-related competitive endogenous RNA (ceRNA) regulatory network of lncRNA/circRNA-miRNA-mRNA with 561 edges and 434 nodes (188 lncRNAs, 5 circRNAs, 191 miRNAs, and 50 mRNAs) and identified two hub lncRNAs (MSTRG.11908.1 and MSTRG.8791.1) and four hub miRNAs (hbr-miR156, miR156-x, miRf10477-y, and novel-m0452-3p). Notably, the lncRNA-miR156/157-SPL module containing three hubs probably plays a crucial role in TPD onset. The expression of network hubs and the lncRNA-miR156/157-SPL module were further validated by qRT-PCR. Our results reveal the TPD-associated ceRNA regulatory network of lncRNA/circRNA-miRNA-mRNA in latex and lay a foundation for further investigation of molecular regulatory mechanisms for TPD onset in H. brasiliensis.

Transcriptional signature of islet neogenesis-associated protein peptide-treated rat pancreatic islets reveals induction of novel long non-coding RNAs.

Background: Diabetes mellitus is characterized by chronic hyperglycemia with loss of ß-cell function and mass. An attractive therapeutic approach to treat patients with diabetes in a non-invasive way is to harness the innate regenerative potential of the pancreas. The Islet Neogenesis-Associated Protein pentadecapeptide (INGAP-PP) has been shown to induce ß-cell regeneration and improve their function in rodents. To investigate its possible mechanism of action, we report here the global transcriptional effects induced by the short-term INGAP-PP in vitro treatment of adult rat pancreatic islets. Methods and findings: Rat pancreatic islets were cultured in vitro in the presence of INGAP-PP for 4 days, and RNA-seq was generated from triplicate treated and control islet samples. We performed a de novo rat gene annotation based on the alignment of RNA-seq reads. The list of INGAP-PP-regulated genes was integrated with epigenomic data. Using the new gene annotation generated in this work, we quantified RNA-seq data profiled in INS-1 cells treated with IL1ß, IL1ß+Calcipotriol (a vitamin D agonist) or vehicle, and single-cell RNA-seq data profiled in rat pancreatic islets. We found 1,669 differentially expressed genes by INGAP-PP treatment, including dozens of previously unannotated rat transcripts. Genes differentially expressed by the INGAP-PP treatment included a subset of upregulated transcripts that are associated with vitamin D receptor activation. Supported by epigenomic and single-cell RNA-seq data, we identified 9 previously unannotated long noncoding RNAs (lncRNAs) upregulated by INGAP-PP, some of which are also differentially regulated by IL1ß and vitamin D in ß-cells. These include Ri-lnc1, which is enriched in mature ß-cells. Conclusions: Our results reveal the transcriptional program that could explain the enhancement of INGAP-PP-mediated physiological effects on ß-cell mass and function. We identified novel lncRNAs that are induced by INGAP-PP in rat islets, some of which are selectively expressed in pancreatic ß-cells and downregulated by IL1ß treatment of INS-1 cells. Our results suggest a relevant function for Ri-lnc1 in ß-cells. These findings are expected to provide the basis for a deeper understanding of islet translational results from rodents to humans, with the ultimate goal of designing new therapies for people with diabetes.

Metastasis-associated lung adenocarcinoma transcript 1 molecular mechanisms in gastric cancer progression.

Gastric cancer (GC) remains among the most common cancers worldwide with a high mortality-to-incidence ratio. Accumulated evidence suggests that long noncoding RNAs (lncRNAs) are involved in gastric carcinogenesis. These transcripts are longer than 200 nucleotides and modulate gene expression at multiple molecular levels, inducing or inhibiting biological processes and diseases. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is one of the best-studied lncRNAs with comprehensive actions contributing to cancer progression. This lncRNA regulates gene expression at the transcriptional and posttranscriptional levels through interactions with microRNAs and proteins. In the present review, we discussed the molecular mechanism of MALAT1 and summarized the current knowledge of its expression in GC. Moreover, we highlighted the potential use of MALAT1 as a biomarker, including liquid biopsy.

Revealing metastatic castration-resistant prostate cancer master regulator through lncRNAs-centered regulatory network.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive form of cancer unresponsive to androgen deprivation therapy (ADT) that spreads quickly to other organs. Despite reduced androgen levels after ADT, mCRPC development and lethality continues to be conducted by the androgen receptor (AR) axis. The maintenance of AR signaling in mCRPC is a result of AR alterations, androgen intratumoral production, and the action of regulatory elements, such as noncoding RNAs (ncRNAs). ncRNAs are key elements in cancer signaling, acting in tumor growth, metabolic reprogramming, and tumor progression. In prostate cancer (PCa), the ncRNAs have been reported to be associated with AR expression, PCa proliferation, and castration resistance. In this study, we aimed to reconstruct the lncRNA-centered regulatory network of mCRPC and identify the lncRNAs which act as master regulators (MRs). METHODS: We used publicly available RNA-sequencing to infer the regulatory network of lncRNAs in mCRPC. Five gene signatures were employed to conduct the master regulator analysis. Inferred MRs were then subjected to functional enrichment and symbolic regression modeling. The latter approach was applied to identify the lncRNAs with greater predictive capacity and potential as a biomarker in mCRPC. RESULTS: We identified 31 lncRNAs involved in cellular proliferation, tumor metabolism, and invasion-metastasis cascade. SNHG18 and HELLPAR were the highlights of our results. SNHG18 was downregulated in mCRPC and enriched to metastasis signatures. It accurately distinguished both mCRPC and primary CRPC from normal tissue and was associated with epithelial-mesenchymal transition (EMT) and cell-matrix adhesion pathways. HELLPAR consistently distinguished mCRPC from primary CRPC and normal tissue using only its expression. CONCLUSION: Our results contribute to understanding the regulatory behavior of lncRNAs in mCRPC and indicate SNHG18 and HELLPAR as master regulators and potential new diagnostic targets in this tumor.

The role of LncRNA LBX2-AS1 in cancers: functions, mechanisms and potential clinical utility.

Increasingly advanced biology technique has revealed that long non-coding RNAs (lncRNA) as critical factors that exert significant regulatory effects on biological functions by modulating gene transcription, epigenetic modifications and protein translation. A newly emerging lncRNA, ladybird homeobox 2 (LBX2)-antisense RNA 1 (LBX2-AS1), was found to be highly expressed in various tumors. Moreover, it is functionally linked to the regulation of essential tumor-related biological processes, such as cell proliferation and apoptosis, through interactions with multiple signaling molecules/pathways. The important roles played by LBX2-AS1 in cancer initiation and progression suggest that this lncRNA has enormous clinical potential for use as a novel biomarker or therapeutic target. In this article, we retrospectively review the latest advances in research exploring the roles of the lncRNA LBX2-AS1 in oncology field, highlighting its involvement in a comprehensive network of molecular mechanisms underlying diverse cancers and examining its potential applications in clinical practice.

The Arabidopsis APOLO and human UPAT sequence-unrelated long noncoding RNAs can modulate DNA and histone methylation machineries in plants.

BACKGROUND: RNA-DNA hybrid (R-loop)-associated long noncoding RNAs (lncRNAs), including the Arabidopsis lncRNA AUXIN-REGULATED PROMOTER LOOP (APOLO), are emerging as important regulators of three-dimensional chromatin conformation and gene transcriptional activity. RESULTS: Here, we show that in addition to the PRC1-component LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), APOLO interacts with the methylcytosine-binding protein VARIANT IN METHYLATION 1 (VIM1), a conserved homolog of the mammalian DNA methylation regulator UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1). The APOLO-VIM1-LHP1 complex directly regulates the transcription of the auxin biosynthesis gene YUCCA2 by dynamically determining DNA methylation and H3K27me3 deposition over its promoter during the plant thermomorphogenic response. Strikingly, we demonstrate that the lncRNA UHRF1 Protein Associated Transcript (UPAT), a direct interactor of UHRF1 in humans, can be recognized by VIM1 and LHP1 in plant cells, despite the lack of sequence homology between UPAT and APOLO. In addition, we show that increased levels of APOLO or UPAT hamper VIM1 and LHP1 binding to YUCCA2 promoter and globally alter the Arabidopsis transcriptome in a similar manner. CONCLUSIONS: Collectively, our results uncover a new mechanism in which a plant lncRNA coordinates Polycomb action and DNA methylation through the interaction with VIM1, and indicates that evolutionary unrelated lncRNAs with potentially conserved structures may exert similar functions by interacting with homolog partners.

Emerging Functions of lncRNA Loci beyond the Transcript Itself.

Thousands of long noncoding RNAs (lncRNAs) are actively transcribed in mammalian genomes. This class of RNAs has important regulatory functions in a broad range of cellular processes and diseases. Numerous lncRNAs have been demonstrated to mediate gene regulation through RNA-based mechanisms. Simultaneously, non-functional lncRNA transcripts derived from the activity of lncRNA loci have been identified, which underpin the notion that a considerable fraction of lncRNA loci exert regulatory functions through mechanisms associated with the production or the activity of lncRNA loci beyond the synthesized transcripts. We particularly distinguish two main RNA-independent components associated with regulatory effects; the act of transcription and the activity of DNA regulatory elements. We describe the experimental approaches to distinguish and understand the functional mechanisms derived from lncRNA loci. These scenarios reveal emerging mechanisms important to understanding the lncRNA implications in genome biology.

Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma.

PURPOSE: Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. METHODS: We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. RESULTS: We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. CONCLUSIONS: Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.

Insight Into the Long Noncoding RNA and mRNA Coexpression Profile in the Human Blood Transcriptome Upon Leishmania infantum Infection.

Visceral leishmaniasis (VL) is a vector-borne infectious disease that can be potentially fatal if left untreated. In Brazil, it is caused by Leishmania infantum parasites. Blood transcriptomics allows us to assess the molecular mechanisms involved in the immunopathological processes of several clinical conditions, namely, parasitic diseases. Here, we performed mRNA sequencing of peripheral blood from patients with visceral leishmaniasis during the active phase of the disease and six months after successful treatment, when the patients were considered clinically cured. To strengthen the study, the RNA-seq data analysis included two other non-diseased groups composed of healthy uninfected volunteers and asymptomatic individuals. We identified thousands of differentially expressed genes between VL patients and non-diseased groups. Overall, pathway analysis corroborated the importance of signaling involving interferons, chemokines, Toll-like receptors and the neutrophil response. Cellular deconvolution of gene expression profiles was able to discriminate cellular subtypes, highlighting the contribution of plasma cells and NK cells in the course of the disease. Beyond the biological processes involved in the immunopathology of VL revealed by the expression of protein coding genes (PCGs), we observed a significant participation of long noncoding RNAs (lncRNAs) in our blood transcriptome dataset. Genome-wide analysis of lncRNAs expression in VL has never been performed. lncRNAs have been considered key regulators of disease progression, mainly in cancers; however, their pattern regulation may also help to understand the complexity and heterogeneity of host immune responses elicited by L. infantum infections in humans. Among our findings, we identified lncRNAs such as IL21-AS1, MIR4435-2HG and LINC01501 and coexpressed lncRNA/mRNA pairs such as CA3-AS1/CA1, GASAL1/IFNG and LINC01127/IL1R1-IL1R2. Thus, for the first time, we present an integrated analysis of PCGs and lncRNAs by exploring the lncRNA-mRNA coexpression profile of VL to provide insights into the regulatory gene network involved in the development of this inflammatory and infectious disease.

Diagnostic and prognostic significance of long noncoding RNA LINC00173 in patients with melanoma

SUMMARY OBJECTIVE: A growing volume of literature has suggested long noncoding RNAs (lncRNAs) as important players in tumor progression. In this study, we aimed to investigate the expression and prognostic value of lncRNA LINC00173 (LINC00173) in melanoma. METHODS: LINC00173 expression was measured in 163 paired cancerous and noncancerous specimen samples by real-time polymerase chain reaction. The correlations between LINC00173 expression with clinicopathological characteristics and prognosis were analyzed by chi-square test, log-rank test, and multivariate survival analysis. Receiver-operating characteristic curves were used for the assessment of the diagnostic value of LINC00173 for melanoma patients. RESULTS: The expression level of LINC00173 in melanoma specimens was distinctly higher than that in adjacent non-neoplasm specimens (p<0.01). Besides, LINC00173 was expressed more frequently in patients with advanced melanoma than in patients with early melanoma. Multivariate assays confirmed that LINC00173 expression level was an independent prognostic predictor of melanoma patients (p<0.05). CONCLUSION: Our data indicated that LINC00173 expression could serve as an unfavorable prognostic biomarker for melanoma patients.

Genome-wide identification of lncRNAs, miRNAs, mRNAs and their regulatory networks involved in tapping panel dryness in rubber tree (Hevea brasiliensis).

Noncoding RNAs (ncRNAs) play pivotal roles in various biological processes in plants. However, the role of ncRNAs in tapping panel dryness (TPD) of rubber tree (Hevea brasiliensis Muell. Arg.) is largely unknown. Here, the whole transcriptome analyses of bark tissues from healthy and TPD trees were performed to identify differentially expressed long ncRNAs (DELs), microRNAs/miRNAs (DEMs), genes (DEGs) and their regulatory networks involved in TPD. A total of 263 DELs, 174 DEMs and 1574 DEGs were identified in the bark of TPD tree compared with that of healthy tree. Kyoto Encyclopedia of Genes and Genomes analysis revealed that most of the DEGs and targets of DELs and DEMs were mainly enriched in metabolic pathways, biosynthesis of secondary metabolites and plant hormone signal transduction. Additionally, the majority of DEGs and DELs related to rubber biosynthesis were downregulated in TPD trees. Furthermore, 98 DEGs and 44 DELs were targeted by 54 DEMs, 190 DEGs were identified as putative targets of 56 DELs, and 2 and 44 DELs were predicted as precursors and endogenous target mimics of 2 and 6 DEMs, respectively. Based on these, the DEL-DEM-DEG regulatory network involved in TPD was constructed, and 13 hub DELs, 3 hub DEMs and 2 hub DEGs were identified. The results provide novel insights into the regulatory roles of ncRNAs underlying TPD and lay a foundation for future functional characterization of long ncRNAs, miRNAs and genes involved in TPD in rubber tree.

Oncogenic functions of ZEB1 in pediatric solid cancers: interplays with microRNAs and long noncoding RNAs.

The transcription factor Zinc finger E-box binding 1 (ZEB1) displays a range of regulatory activities in cell function and embryonic development, including driving epithelial-mesenchymal transition. Several aspects of ZEB1 function can be regulated by its functional interactions with noncoding RNA types, namely microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Increasing evidence indicates that ZEB1 importantly influences cancer initiation, tumor progression, metastasis, and resistance to treatment. Cancer is the main disease-related cause of death in children and adolescents. Although the role of ZEB1 in pediatric cancer is still poorly understood, emerging findings have shown that it is expressed and regulates childhood solid tumors including osteosarcoma, retinoblastoma, neuroblastoma, and central nervous system tumors. Here, we review the evidence supporting a role for ZEB1, and its interplays with miRNAs and lncRNAs, in pediatric cancers.

Non-Syndromic Intellectual Disability and Its Pathways: A Long Noncoding RNA Perspective.

Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it difficult to understand its etiology. Long noncoding RNAs (lncRNAs) comprise a large group of transcripts that can act through various mechanisms and be involved in important neurodevelopmental processes. In this sense, comprehending the roles they play in this intricate context is a valuable way of getting new insights about how NS-ID can arise and develop. In this review, we attempt to bring together knowledge available in the literature about lncRNAs involved with molecular and cellular pathways already described in intellectual disability and neural function, to better understand their relevance in NS-ID and the regulatory complexity of this disorder.

Differential Expression of lncRNAs and miRNAs Between Self-Rooting Juvenile and Donor Clones Unveils Novel Insight Into the Molecular Regulation of Rubber Biosynthesis in Hevea brasiliensis.

The rubber tree (Hevea brasiliensis Muell. Arg.) is a tropical tree species that produce natural rubber. Self-rooted juvenile clones (SRJCs) are novel rubber tree planting materials developed through primary somatic embryogenesis. SRJCs have a higher rubber yield compared with donor clones (DCs). The molecular basis underlying increased rubber yield in SRJCs remains largely unknown. Here, the latex from SRJCs and DCs were collected for strand-specific and small RNA-seq methods. A total of 196 differentially expressed long noncoding RNAs (DELs), and 11 differentially expressed microRNAs were identified in latex between SRJCs and DCs. Targeted genes of DELs were markedly enriched for various biological pathways related to plant hormone signal transduction, photosynthesis, glutathione metabolism, and amino acids biosynthesis. DELs probably acted as cis-acting regulation was calculated, and these DELs relevant to potentially regulate rubber biosynthesis, reactive oxygen species metabolism, and epigenetic modification. Furthermore, the DELs acting as microRNA targets were studied. The interaction of microRNA and DELs might involve in the regulation of natural rubber biosynthesis.

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia.

Evidence showing the role of long non-coding RNAs (lncRNAs) in leukemogenesis have emerged in the last decade. It has been proposed that these genes can be used as diagnosis and/or prognosis biomarkers in childhood acute lymphoblastic leukemia (ALL). To know if lncRNAs are associated with early relapse and early mortality, a microarray-based gene expression analysis in children with B-lineage ALL (B-ALL) was conducted. Cox regression analyses were performed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated. LINC00152 and LINC01013 were among the most differentially expressed genes in patients with early relapse and early mortality. For LINC00152 high expression, the risks of relapse and death were HR: 4.16 (95% CI: 1.46-11.86) and HR: 1.99 (95% CI: 0.66-6.02), respectively; for LINC01013 low expression, the risks of relapse and death were HR: 3.03 (95% CI: 1.14-8.05) and HR: 6.87 (95% CI: 1.50-31.48), respectively. These results were adjusted by NCI risk criteria and chemotherapy regimen. The lncRNA-mRNA co-expression analysis showed that LINC00152 potentially regulates genes involved in cell substrate adhesion and peptidyl-tyrosine autophosphorylation biological processes. The results of the present study point out that LINC00152 could be a potential biomarker of relapse in children with B-ALL.

Regulatory SNP rs5743417 impairs constitutive expression of human ß-defensin 1 and has high frequency in Africans and Afro-Americans.

The prediction of regulatory single nucleotide polymorphisms (rSNPs) in proximal promoters of disease-related genes could be a useful tool for personalized medicine in both patient stratification and customized therapy. Using our previously reported method of rSNPs prediction (currently a software called SNPClinic v.1.0) as well as with PredictSNP tool, we performed in silico prediction of regulatory SNPs in the antimicrobial peptide human ß-defensin 1 gene in three human cell lines from 1,000 Genomes Project (1kGP), namely A549 (epithelial cell line), HL-60 (neutrophils) and TH 1 (lymphocytes). These predictions were run in a proximal pseudo-promoter comprising all common alleles on each polymorphic site according to the 1,000 Genomes Project data (1kGP: ALL). Plasmid vectors containing either the major or the minor allele of a putative rSNP rs5743417 (categorized as regulatory by SNPClinic and confirmed by PredictSNP) and a non-rSNP negative control were transfected to lung A549 human epithelial cell line. We assessed functionality of rSNPs by qPCR using the Pfaffl method. In A549 cells, minor allele of the SNP rs5743417 G→A showed a significant reduction in gene expression, diminishing DEFB1 transcription by 33% when compared with the G major allele (p-value = .03). SNP rs5743417 minor allele has high frequency in Gambians (8%, 1kGP population: GWD) and Afro-Americans (3.3%, 1kGP population: ASW). This SNP alters three transcription factors binding sites (TFBSs) comprising SREBP2 (sterols and haematopoietic pathways), CREB1 (cAMP, insulin and TNF pathways) and JUND (apoptosis, senescence and stress pathways) in the proximal promoter of DEFB1. Further in silico analysis reveals that this SNP also overlaps with GS1-24F4.2, a lincRNA gene complementary to the X Kell blood group related 5 (XKR5) mRNA. The potential clinical impact of the altered constitutive expression of DEFB1 caused by rSNP rs5743417 in DEFB1-associated diseases as tuberculosis, COPD, asthma, cystic fibrosis and cancer in African and Afro-American populations deserves further research.