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1.
Yakugaku Zasshi ; 140(5): 687-700, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378673

RESUMO

Recent advances in high-throughput technologies have revealed that 75% of the human genome is transcribed to RNA, whereas only 3% of transcripts are translated into proteins. Consequently, many long non-coding RNAs (lncRNAs) have been identified, which has improved our understanding of the complexity of biological processes. LncRNAs comprise multiple classes of RNA transcripts that regulate the transcription, stability and translation of protein-coding genes in a genome. Natural antisense transcripts (NATs) form one such class, and the GENCODE v30 catalog contains 16193 lncRNA loci, of which 5611 are antisense loci. This review outlines our emerging understanding of lncRNAs, with a particular focus on how lncRNAs regulate gene expression using interferon-α1 (IFN-α1) mRNA and its antisense partner IFN-α1 antisense (as)RNA as an example. We have identified and characterized the asRNA that determines post-transcriptional IFN-α1 mRNA levels. IFN-α1 asRNA stabilizes IFN-α1 mRNA by cytoplasmic sense-antisense duplex formation, which may enhance the accessibility of an RNA stabilizer protein or decrease the affinity of an RNA decay factor for the RNA. IFN-α1 asRNA can also act as competing molecules in the competing endogenous (ce)RNA network with other members of the IFNA multigene family mRNAs/asRNAs, and other cellular mRNA transcripts. Furthermore, antisense oligoribonucleotides representing functional domains of IFN-α1 asRNA inhibit influenza virus proliferation in the respiratory tract of virus-infected animals. Thus, these findings support, at least in part, the rationale that dissecting the activity of NAT on gene expression regulation promises to reveal previously unanticipated biology, with potential to provide new therapeutic approaches to diseases.


Assuntos
Regulação da Expressão Gênica/genética , RNA Antissenso/fisiologia , RNA não Traduzido/fisiologia , Animais , Genoma Humano/genética , Humanos , Interferon-alfa/química , Interferon-alfa/genética , Família Multigênica , Oligorribonucleotídeos Antissenso/fisiologia , Orthomyxoviridae/fisiologia , Estabilidade de RNA , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Sistema Respiratório/virologia , Transcrição Genética/genética , Replicação Viral
3.
Nat Commun ; 11(1): 168, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924754

RESUMO

Variations in transcription start site (TSS) selection reflect diversity of preinitiation complexes and can impact on post-transcriptional RNA fates. Most metazoan polymerase II-transcribed genes carry canonical initiation with pyrimidine/purine (YR) dinucleotide, while translation machinery-associated genes carry polypyrimidine initiator (5'-TOP or TCT). By addressing the developmental regulation of TSS selection in zebrafish we uncovered a class of dual-initiation promoters in thousands of genes, including snoRNA host genes. 5'-TOP/TCT initiation is intertwined with canonical initiation and used divergently in hundreds of dual-initiation promoters during maternal to zygotic transition. Dual-initiation in snoRNA host genes selectively generates host and snoRNA with often different spatio-temporal expression. Dual-initiation promoters are pervasive in human and fruit fly, reflecting evolutionary conservation. We propose that dual-initiation on shared promoters represents a composite promoter architecture, which can function both coordinately and divergently to diversify RNAs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Regiões Promotoras Genéticas/genética , Sítio de Iniciação de Transcrição , Transcrição Genética , Animais , Sequência de Bases , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Humanos , RNA/genética , RNA/fisiologia , RNA Nucleolar Pequeno/genética , RNA Nucleolar Pequeno/metabolismo , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/fisiologia , RNA não Traduzido/genética , RNA não Traduzido/fisiologia , Elementos Reguladores de Transcrição , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Zigoto
4.
Biochim Biophys Acta Gene Regul Mech ; 1863(4): 194378, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31048026

RESUMO

Paradigm shifting studies especially involving non-coding RNAs (ncRNAs) during last few decades have significantly changed the scientific perspectives regarding the complexity of cellular signalling pathways. Several studies have shown that the non-coding RNAs, initially ignored as transcriptional noise or products of erroneous transcription; actually regulate plethora of biological phenomena ranging from developmental processes to various diseases including cancer. Current strategies that are employed for the management of various cancers including that of breast fall short when their undesired side effects like Cancer Stem Cells (CSC) enrichment, low recurrence-free survival and development of drug resistance are taken into consideration. This review aims at exploring the potential role of ncRNAs as therapeutics in breast cancer, by providing a comprehensive understanding of their mechanism of action and function and their crucial contribution in regulating various aspects of breast cancer progression such as cell proliferation, angiogenesis, EMT, CSCs, drug resistance and metastasis. In addition, we also provide information about various strategies that can be employed or are under development to explore them as potential moieties that may be used for therapeutic intervention in breast cancer.


Assuntos
Neoplasias da Mama/genética , RNA não Traduzido/fisiologia , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/genética , RNA Longo não Codificante/metabolismo , RNA não Traduzido/metabolismo , Microambiente Tumoral
5.
Hepatology ; 71(1): 130-147, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31148183

RESUMO

Hepatocellular carcinoma (HCC) is one of the fastest-rising causes of cancer-related death worldwide, but its deficiency of specific biomarkers and therapeutic targets in the early stages lead to severe inadequacy in the early diagnosis and treatment of HCC. Covalently closed circular RNA (circRNA), which was once considered an aberrant splicing by-product, is now drawing new interest in cancer research because of its remarkable functionality. Beneath the surface of the dominant functional proteins events, a hidden circRNA-centric noncoding regulatory RNAs network active in the very early stage of HCC is here revealed by a genome-wide analysis of mRNA, circRNA, and microRNA (miRNA) expression profiles. Circ-CDYL (chromodomain Y like) is specifically up-regulated in the early stages of HCC and therefore contributes to the properties of epithelial cell adhesion molecule (EPCAM)-positive liver tumor-initiating cells. Circ-CDYL interacts with mRNAs encoding hepatoma-derived growth factor (HDGF) and hypoxia-inducible factor asparagine hydroxylase (HIF1AN) by acting as the sponge of miR-892a and miR-328-3p, respectively. Subsequently, activation of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase-mechanistic target of rapamycin kinase complex 1/ß-catenin and NOTCH2 pathways, which promote the expression of the effect proteins, baculoviral IAP repeat containing 5 (BIRC5 or SURVIVIN) and MYC proto-oncogene, is influenced by circ-CDYL. A treatment incorporating circ-CDYL interference and traditional enzyme inhibitors targeting PI3K and HIF1AN demonstrated highly effective inhibition of stem-like characteristics and tumor growth in HCC. Finally, we demonstrated that circ-CDYL expression or which combined with HDGF and HIF1AN are both independent markers for discrimination of early stages of HCC with the odds ratios of 1.09 (95% confidence interval [CI], 1.02-1.17) and 124.58 (95% CI, 13.26-1170.56), respectively. Conclusion: These findings uncover a circRNA-centric noncoding regulatory RNAs network in the early stages of HCC and thus provide a possibility for surveillance and early treatment of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas Correpressoras/fisiologia , Hidroliases/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , RNA Circular/fisiologia , RNA não Traduzido/fisiologia , Humanos , Estadiamento de Neoplasias , Células Tumorais Cultivadas
6.
Biochim Biophys Acta Gene Regul Mech ; 1863(1): 194477, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884117

RESUMO

Cyanobacteria are photosynthetic bacteria that populate widely different habitats. Accordingly, cyanobacteria exhibit a wide spectrum of lifestyles, physiologies, and morphologies and possess genome sizes and gene numbers which may vary by up to a factor of ten within the phylum. Consequently, large differences exist between individual species in the size and complexity of their regulatory networks. Several non-coding RNAs have been identified that play crucial roles in the acclimation responses of cyanobacteria to changes in the environment. Some of these regulatory RNAs are conserved throughout the cyanobacterial phylum, while others exist only in a few taxa. Here we give an overview on characterized regulatory RNAs in cyanobacteria, with a focus on regulators of photosynthesis, carbon and nitrogen metabolism. However, chances are high that these regulators represent just the tip of the iceberg.


Assuntos
Carbono/metabolismo , Cianobactérias/genética , Nitrogênio/metabolismo , Fotossíntese/genética , RNA não Traduzido/fisiologia , Cianobactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Ferro/metabolismo , Fixação de Nitrogênio/genética , RNA Antissenso/biossíntese , Pequeno RNA não Traduzido/biossíntese , Pequeno RNA não Traduzido/química , RNA não Traduzido/biossíntese , Riboswitch
7.
Proc Natl Acad Sci U S A ; 116(51): 25392-25394, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31796588

RESUMO

The oncogenic gammaherpesviruses, including human Epstein-Barr virus (EBV), human Kaposi's sarcoma-associated herpesvirus (KSHV), and murine gammaherpesvirus 68 (MHV68, γHV68, MuHV-4) establish life-long latency in circulating B cells. The precise determinants that mediate in vivo gammaherpesvirus latency and tumorigenesis remain unclear. The EBV-encoded RNAs (EBERs) are among the first noncoding RNAs ever identified and have been the subject of decades of studies; however, their biological roles during in vivo infection remain unknown. Herein, we use a series of refined virus mutants to define the active isoform of MHV68 noncoding RNA TMER4 and demonstrate that EBV EBER1 functionally conserves this activity in vivo to promote egress of infected B cells from lymph nodes into peripheral circulation.


Assuntos
Gammaherpesvirinae/genética , RNA não Traduzido , RNA Viral , Liberação de Vírus/genética , Animais , Células Cultivadas , Infecções por Herpesviridae/virologia , Camundongos , Conformação de Ácido Nucleico , RNA não Traduzido/química , RNA não Traduzido/genética , RNA não Traduzido/fisiologia , RNA Viral/química , RNA Viral/genética , RNA Viral/fisiologia , Baço/citologia , Baço/virologia , Latência Viral/genética
8.
Cells ; 8(12)2019 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-31847392

RESUMO

The intricate molecular network shared between diabetes mellitus (DM) and cancer has been broadly understood. DM has been associated with several hormone-dependent malignancies, including breast, pancreatic, and colorectal cancer (CRC). Insulin resistance, hyperglycemia, and inflammation are the main pathophysiological mechanisms linking DM to cancer. Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are widely appreciated as pervasive regulators of gene expression, governing the evolution of metabolic disorders, including DM and cancer. The ways ncRNAs affect the development of DM complicated with cancer have only started to be revealed in recent years. Insulin-like growth factor 1 receptor (IGF-1R) signaling is a master regulator of pathophysiological processes directing DM and cancer. In this review, we briefly summarize a number of well-known miRNAs and lncRNAs that regulate the IGF-1R in DM and cancer, respectively, and further discuss the potential underlying molecular pathogenesis of this disease association.


Assuntos
Diabetes Mellitus/genética , Neoplasias/genética , Receptor IGF Tipo 1/genética , Diabetes Mellitus/fisiopatologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/genética , Neoplasias/fisiopatologia , RNA Longo não Codificante/genética , RNA não Traduzido/genética , RNA não Traduzido/fisiologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/genética
9.
J Zhejiang Univ Sci B ; 20(11): 920-927, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595728

RESUMO

Noncoding RNAs (ncRNAs) have played a critical role in cellular biological functions. Recently, some peptides or proteins originating from annotated ncRNAs were identified in organism development and various diseases. Here, we briefly review several novel peptides translated by annotated ncRNAs and related key functions. In addition, we summarize the potential mechanism of bifunctional ncRNAs and propose a specific "switch" triggering the transformation from the noncoding to the coding state under certain stimuli or cellular stress. The coding properties of ncRNAs and their peptide products may provide a novel horizon in proteomic research and can be regarded as a potential therapeutic target for the treatment of various diseases.


Assuntos
Biossíntese de Proteínas , RNA não Traduzido/fisiologia , Animais , Cálcio/metabolismo , Humanos , Fases de Leitura Aberta , RNA Mensageiro/genética
10.
Eur Rev Med Pharmacol Sci ; 23(19): 8175-8185, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31646607

RESUMO

OBJECTIVE: Osteoarthritis (OA) is a common disease in articular cartilages. It has been reported that long non-coding RNAs (lncRNAs) play an important role in various pathological processes of OA. However, the role of PART1 in OA development is unclear. PATIENTS AND METHODS: The expression levels of PART1 and miR-373-3p were detected in cartilage tissues and chondrocytes using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was determined by flow cytometry and Western blot assay. The expression of extracellular matrix (ECM)-related proteins was examined by Western blot assay. Expression of SRY-related high-mobility group box 4 (SOX4) was measured by qRT-PCR or Western blot assay. The interactions among PART1, miR-373-3p, and SOX4 were predicted using starBase v2.0 database and confirmed by Dual-Luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS: PART1 and SOX4 were up-regulated while miR-373-3p was down-regulated in OA cartilage tissues and chondrocytes. PART1 silencing hindered cell proliferation and ECM degradation, and triggered cell apoptosis in OA chondrocytes. PART1 modulated SOX4 expression by targeting miR-373-3p. Inhibition of miR-373-3p restored the regulation of cell proliferation, ECM degradation, and apoptosis induced by interfering PART1. Upregulation of SOX4 restored the effects on OA progression induced by inhibiting PART1. CONCLUSIONS: PART1 promoted OA progression by regulating miR-373-3p/SOX4 axis, providing an effective therapeutic target for osteoarthritis.


Assuntos
Condrócitos/fisiologia , Matriz Extracelular/metabolismo , MicroRNAs/metabolismo , Osteoartrite/metabolismo , RNA Longo não Codificante/metabolismo , RNA não Traduzido/metabolismo , Fatores de Transcrição SOXC/metabolismo , Apoptose/fisiologia , Western Blotting , Cartilagem/metabolismo , Cartilagem/fisiologia , Proliferação de Células/fisiologia , Condrócitos/metabolismo , Citometria de Fluxo , Humanos , Imunoprecipitação , Osteoartrite/etiologia , RNA Longo não Codificante/fisiologia , RNA não Traduzido/fisiologia , Reação em Cadeia da Polimerase em Tempo Real
11.
Biochem Pharmacol ; 169: 113638, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31518552

RESUMO

Accumulating evidence has demonstrated that genome-derived noncoding RNAs (ncRNAs) play important roles in modulating inter-individual variations observed in drug metabolism and disposition by controlling the expression of genes coding drug metabolizing enzymes and transporters (DMETs) and relevant nuclear receptors (NRs). With the understanding of novel ncRNA regulatory mechanisms and significance in the control of disease initiation and progression, RNA-based therapies are under active investigation that may expand the druggable targets from conventional proteins to RNAs and the genome for the treatment of human diseases. Herein we provide an overview of research strategies, approaches and their limitations in biochemical and pharmacological studies pertaining to ncRNA functions in the regulation of drug and nutrient metabolism and disposition, and discussion on the promise and challenges in developing RNA therapeutics.


Assuntos
Preparações Farmacêuticas/metabolismo , RNA não Traduzido/fisiologia , Bioengenharia , Citocromo P-450 CYP2E1/genética , Desenvolvimento de Medicamentos , Humanos , Nutrientes/metabolismo , RNA não Traduzido/uso terapêutico , Ribonucleoproteínas/fisiologia
12.
Cell Mol Life Sci ; 76(21): 4203-4219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300868

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular/métodos , RNA Neoplásico/metabolismo , RNA não Traduzido/metabolismo
13.
BMC Genomics ; 20(1): 512, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221080

RESUMO

BACKGROUND: Dermal papilla cells (DPCs), the "signaling center" of hair follicle (HF), delicately master continual growth of hair in mammals including cashmere, the fine fiber annually produced by secondary HF embedded in cashmere goat skins. Such unparalleled capacity bases on their exquisite character in instructing the cellular activity of hair-forming keratinocytes via secreting numerous molecular signals. Past studies suggested microRNA (miRNAs) and long non-coding RNAs (lncRNAs) play essential roles in a wide variety of biological process, including HF cycling. However, their roles and related molecular mechanisms in modulating DPCs secretory activities are still poorly understood. RESULTS: Here, we separately cultivated DPCs and their functionally and morphologically distinct dermal fibroblasts (DFs) from cashmere goat skins at anagen. With the advantage of high throughput RNA-seq, we synchronously identified 2540 lncRNAs and 536 miRNAs from two types of cellular samples at 4th passages. Compared with DFs, 1286 mRNAs, 18 lncRNAs, and 42 miRNAs were upregulated, while 1254 mRNAs, 53 lncRNAs and 44 miRNAs were downregulated in DPCs. Through overlapping with mice data, we ultimately defined 25 core signatures of DPCs, including HOXC8 and RSPO1, two crucial activators for hair follicle stem cells (HFSCs). Subsequently, we emphatically investigated the impacts of miRNAs and lncRNAs (cis- and trans- acting) on the genes, indicating that ncRNAs extensively exert negative and positive effects on their expressions. Furthermore, we screened lncRNAs acting as competing endogenous RNAs (ceRNAs) to sponge miRNAs and relief their repressive effects on targeted genes, and constructed related lncRNAs-miRNAs-HOXC8/RSPO1 interactive lines using bioinformatic tools. As a result, XR_310320.3-chi-miR-144-5p-HOXC8, XR_311077.2-novel_624-RSPO1 and others lines appeared, displaying that lncRNAs might serve as ceRNAs to indirectly adjust HFSCs status in hair growth. CONCLUSION: The present study provides an unprecedented inventory of lncRNAs, miRNAs and mRNAs in goat DPCs and DFs. We also exhibit some miRNAs and lncRNAs potentially participate in the modulation of HFSCs activation via delicately adjusting core signatures of DPCs. Our report shines new light on the latent roles and underlying molecular mechanisms of ncRNAs on hair growth.


Assuntos
Cabras/genética , Folículo Piloso/metabolismo , RNA Mensageiro/fisiologia , RNA não Traduzido/fisiologia , Animais , Derme/citologia , Feminino , Fibroblastos/metabolismo , Cabras/metabolismo , Cabelo/crescimento & desenvolvimento , Proteínas de Homeodomínio/genética , Humanos , Camundongos , MicroRNAs/metabolismo , Pele/citologia , Trombospondinas/genética , Transcriptoma
14.
Nat Protoc ; 14(5): 1489-1508, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962605

RESUMO

Non-coding RNA (ncRNA) molecules have been shown to play a variety of cellular roles; however, the contributions of different types of RNA to specific phenomena are often hard to dissect. To study the role of RNA in the assembly of DNA damage response (DDR) foci, we developed the RNase A treatment and reconstitution (RATaR) method, in which cells are mildly permeabilized, incubated with recombinant RNase A and subsequently reconstituted with different RNA species, under conditions of RNase A inactivation and inhibition of endogenous transcription. The block of transcription right after RNase A removal represents a key innovation of RATaR, preventing potential contributions of endogenously neo-synthesized transcripts to the phenotypes studied. A critical aspect of this technique is the balance between sufficient permeabilization of membranes to allow enzyme/RNA access into the cell nucleus and cell viability. Here, we present our protocol for RNA-dependent DDR foci disassembly and reassembly using fluorescent DDR RNAs (DDRNAs) in NIH2/4 cells, an engineered NIH3T3-derived cell line. The use of sequence-specific, fluorescent RNA molecules permits the concomitant determination of their subcellular localization and biological functions. We also outline adaptations of RATaR when implemented in different cell lines exposed to various genotoxic treatments, such as γ-radiation, restriction enzymes and telomere deprotection. In all these cases, the entire procedure can be completed within 2 h without the need for special equipment or uncommon skills. We believe this technique will prove useful for investigating the contribution of RNA to a variety of relevant cellular processes.


Assuntos
Dano ao DNA , Reparo do DNA , RNA não Traduzido , Ribonuclease Pancreático/metabolismo , Animais , Dano ao DNA/genética , Dano ao DNA/fisiologia , Reparo do DNA/genética , Reparo do DNA/fisiologia , Técnicas Genéticas , Células HeLa , Humanos , Camundongos , Células NIH 3T3 , RNA/análise , RNA/genética , RNA/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/fisiologia
15.
Cell ; 176(5): 1054-1067.e12, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30773316

RESUMO

Vault RNAs (vtRNA) are small non-coding RNAs transcribed by RNA polymerase III found in many eukaryotes. Although they have been linked to drug resistance, apoptosis, and viral replication, their molecular functions remain unclear. Here, we show that vault RNAs directly bind the autophagy receptor sequestosome-1/p62 in human and murine cells. Overexpression of human vtRNA1-1 inhibits, while its antisense LNA-mediated knockdown enhances p62-dependent autophagy. Starvation of cells reduces the steady-state and p62-bound levels of vault RNA1-1 and induces autophagy. Mechanistically, p62 mutants that fail to bind vtRNAs display increased p62 homo-oligomerization and augmented interaction with autophagic effectors. Thus, vtRNA1-1 directly regulates selective autophagy by binding p62 and interference with oligomerization, a critical step of p62 function. Our data uncover a striking example of the potential of RNA to control protein functions directly, as previously recognized for protein-protein interactions and post-translational modifications.


Assuntos
Autofagia/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Células HeLa , Humanos , Camundongos , Células RAW 264.7 , RNA/metabolismo , RNA não Traduzido/metabolismo , RNA não Traduzido/fisiologia , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo
16.
Biol Psychiatry ; 85(5): 417-424, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600091

RESUMO

BACKGROUND: Previous findings suggest that differences in brain expression of a human-specific long intergenic noncoding RNA (LINC01268; GRCh37/hg19: LOC285758) may be linked to suicide by violent methods. We sought to replicate and extend these findings in a new sample and translate the results to the behavioral level in living healthy subjects. METHODS: We examined RNA sequencing data in human brains to confirm the prior postmortem association of the long intergenic noncoding RNA specifically with suicide by violent means. In addition, we used a genetic variant associated with LINC01268 expression to detect association in healthy subjects with trait aggression and with in vivo prefrontal physiology related to behavioral control. Finally, we performed weighted gene coexpression network analysis and gene ontology analysis to identify biological processes associated with a LINC01268 coexpression network. RESULTS: In the replication sample, prefrontal expression of LINC01268 was again higher in suicides by violent means (n = 65) than in both nonsuicides (n = 78; p = 1.29 × 10-6) and suicides by nonviolent means (n = 46; p = 1.4 × 10-6). In the living cohort, carriers of the minor allele of a single nucleotide polymorphism associated with increased LINC01268 expression in brain scored higher on a lifetime aggression questionnaire and show diminished engagement of prefrontal cortex (Brodmann area 10) when viewing angry faces during functional magnetic resonance imaging. Weighted gene coexpression network analysis highlighted the immune response. CONCLUSIONS: These results suggest that LINC01268 influences emotional regulation, aggressive behavior, and suicide by violent means; the underlying biological dynamics may include modulation of genes potentially engaged in the immune response.


Assuntos
Agressão/fisiologia , Encéfalo/metabolismo , Córtex Pré-Frontal/fisiologia , RNA não Traduzido/biossíntese , RNA não Traduzido/fisiologia , Suicídio/psicologia , Violência , Adulto , Causas de Morte , Feminino , Neuroimagem Funcional , Redes Reguladoras de Genes/genética , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Fenótipo , Análise de Sequência de RNA
17.
Arch Pharm Res ; 42(1): 48-62, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30610616

RESUMO

Hepatocellular carcinoma (HCC) is a tumor with poor prognosis and frequently aggressive. The development of HCC is associated with fibrosis and cirrhosis, which mainly results from nonalcoholic fatty liver disease, excessive alcohol consumption, and viral infections. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome, but are not translated into proteins. Recently, ncRNAs emerged as key contributors to tumor development and progression because of their abilities to regulate various targets and modulate cell proliferation, differentiation, apoptosis, and development. In this review, we summarize the frequently activated pathways in HCC and discuss the pathological implications of ncRNAs in the context of human liver disease progression, in particular HCC development and progression. This review aims to summarize the role of ncRNA dysregulation in the diseases and discuss the diagnostic and therapeutic potentials of ncRNAs.


Assuntos
Carcinoma Hepatocelular/metabolismo , Progressão da Doença , Hepatopatias/metabolismo , Neoplasias Hepáticas/metabolismo , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Hepatopatias/patologia , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/fisiologia , Transdução de Sinais/fisiologia
18.
BMB Rep ; 52(1): 86-108, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30526773

RESUMO

In multi-cellular organisms, the control of gene expression is key not only for development, but also for adult cellular homeostasis, and gene expression has been observed to be deregulated with aging. In this review, we discuss the current knowledge on the transcriptional alterations that have been described to occur with age in metazoans. First, we discuss age-related transcriptional changes in protein-coding genes, the expected functional impact of such changes, and how known pro-longevity interventions impact these changes. Second, we discuss the changes and impact of emerging aspects of transcription in aging, including age-related changes in splicing, lncRNAs and circRNAs. Third, we discuss the changes and potential impact of transcription of transposable elements with aging. Fourth, we highlight small ncRNAs and their potential impact on the regulation of aging phenotypes. Understanding the aging transcriptome will be key to identify important regulatory targets, and ultimately slow-down or reverse aging and extend healthy lifespan in humans. [BMB Reports 2019; 52(1): 86-108].


Assuntos
Envelhecimento/genética , Longevidade/genética , Transcriptoma/genética , Animais , Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Homeostase , Humanos , Fenótipo , RNA não Traduzido/genética , RNA não Traduzido/fisiologia
19.
Plant Biotechnol J ; 17(1): 302-315, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29947466

RESUMO

Lignin provides structural support in perennial woody plants and is a complex phenolic polymer derived from phenylpropanoid pathway. Lignin biosynthesis is regulated by coordinated networks involving transcription factors (TFs), microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). However, the genetic networks underlying the lignin biosynthesis pathway for tree growth and wood properties remain unknown. Here, we used association genetics (additive, dominant and epistasis) and expression quantitative trait nucleotide (eQTN) mapping to decipher the genetic networks for tree growth and wood properties in 435 unrelated individuals of Populus tomentosa. We detected 124 significant associations (P ≤ 6.89E-05) for 10 growth and wood property traits using 30 265 single nucleotide polymorphisms from 203 lignin biosynthetic genes, 81 TF genes, 36 miRNA genes and 71 lncRNA loci, implying their common roles in wood formation. Epistasis analysis uncovered 745 significant pairwise interactions, which helped to construct proposed genetic networks of lignin biosynthesis pathway and found that these regulators might affect phenotypes by linking two lignin biosynthetic genes. eQTNs were used to interpret how causal genes contributed to phenotypes. Lastly, we investigated the possible functions of the genes encoding 4-coumarate: CoA ligase and cinnamate-4-hydroxylase in wood traits using epistasis, eQTN mapping and enzymatic activity assays. Our study provides new insights into the lignin biosynthesis pathway in poplar and enables the novel genetic factors as biomarkers for facilitating genetic improvement of trees.


Assuntos
Genes de Plantas/genética , Lignina/biossíntese , Populus/genética , RNA não Traduzido/genética , Fatores de Transcrição/genética , Madeira/crescimento & desenvolvimento , Genes de Plantas/fisiologia , Desequilíbrio de Ligação/genética , Redes e Vias Metabólicas/genética , MicroRNAs/genética , MicroRNAs/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Populus/crescimento & desenvolvimento , Populus/metabolismo , Locos de Características Quantitativas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia , RNA não Traduzido/fisiologia , Fatores de Transcrição/fisiologia , Transcriptoma , Madeira/metabolismo
20.
Oncol Res ; 27(2): 219-226, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29562954

RESUMO

Breast cancer (BC) is the most common malignant tumor in women. Recently, long noncoding RNAs (lncRNAs) have been proposed as critical regulators in biological processes, including tumorigenesis. FOXC2-AS1, a single antisense oligonucleotide RNA transcribed from the negative strand of forkhead box protein C2 (FOXC2), has been identified as an oncogene in osteosarcoma. In the present study, we investigated the prognosis value and biological role of FOXC2-AS1 in BC. Our findings revealed that FOXC2-AS1 was significantly increased in BC tissues and cell lines, and Kaplan-Meier survival analysis indicated that a high level of FOXC2-AS1 was associated with poor prognosis of BC patients. Loss of function revealed that silenced FOXC2-AS1 significantly suppressed the proliferation ability, and flow cytometric analysis illustrated the influence of FOXC2-AS1 on cell cycle and apoptosis rate. Finally, we found that cyclin D1, cyclin D2, and cyclin D3 were all partly positively modulated by FOXC2-AS1 in BC. Collectively, FOXC2-AS1 may serve as a promising prognostic biomarker and therapeutic target for BC patients.


Assuntos
Neoplasias da Mama/mortalidade , Fatores de Transcrição Forkhead/genética , Oligonucleotídeos Antissenso/metabolismo , Oncogenes/fisiologia , RNA Longo não Codificante/fisiologia , RNA não Traduzido/fisiologia , Apoptose , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fatores de Transcrição Forkhead/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos
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