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1.
Cell ; 178(1): 242-260.e29, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31155234

RESUMO

Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.


Assuntos
Miocárdio/metabolismo , Biossíntese de Proteínas , Adolescente , Adulto , Idoso , Animais , Códon/genética , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ribossomos/genética , Ribossomos/metabolismo , Adulto Jovem
2.
Cell ; 177(4): 865-880.e21, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31031002

RESUMO

Circular RNAs (circRNAs) produced from back-splicing of exons of pre-mRNAs are widely expressed, but current understanding of their functions is limited. These RNAs are stable in general and are thought to have unique structural conformations distinct from their linear RNA cognates. Here, we show that endogenous circRNAs tend to form 16-26 bp imperfect RNA duplexes and act as inhibitors of double-stranded RNA (dsRNA)-activated protein kinase (PKR) related to innate immunity. Upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses. Augmented PKR phosphorylation and circRNA reduction are found in peripheral blood mononuclear cells (PBMCs) derived from patients with autoimmune disease systemic lupus erythematosus (SLE). Importantly, overexpression of the dsRNA-containing circRNA in PBMCs or T cells derived from SLE can alleviate the aberrant PKR activation cascade, thus providing a connection between circRNAs and SLE.


Assuntos
RNA Circular/metabolismo , RNA Circular/fisiologia , eIF-2 Quinase/metabolismo , Adolescente , Adulto , Doenças Autoimunes/genética , Linhagem Celular , Endorribonucleases/metabolismo , Feminino , Humanos , Imunidade Inata/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Pessoa de Meia-Idade , Fosforilação , RNA/metabolismo , Splicing de RNA/genética , Estabilidade de RNA/fisiologia , RNA Circular/genética , RNA de Cadeia Dupla/metabolismo , Viroses/metabolismo , eIF-2 Quinase/imunologia
3.
Mol Cell ; 82(1): 75-89.e9, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34942120

RESUMO

Circular RNAs (circRNAs) are widely expressed in eukaryotes and are regulated in many biological processes. Although several studies indicate their activity as microRNA (miRNA) and protein sponges, little is known about their ability to directly control mRNA homeostasis. We show that the widely expressed circZNF609 directly interacts with several mRNAs and increases their stability and/or translation by favoring the recruitment of the RNA-binding protein ELAVL1. Particularly, the interaction with CKAP5 mRNA, which interestingly overlaps the back-splicing junction, enhances CKAP5 translation, regulating microtubule function in cancer cells and sustaining cell-cycle progression. Finally, we show that circZNF609 downregulation increases the sensitivity of several cancer cell lines to different microtubule-targeting chemotherapeutic drugs and that locked nucleic acid (LNA) protectors against the pairing region on circZNF609 phenocopy such effects. These data set an example of how the small effects tuned by circZNF609/CKAP5 mRNA interaction might have a potent output in tumor growth and drug response.


Assuntos
Carcinogênese , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Neoplasias/metabolismo , RNA Circular/metabolismo , RNA Mensageiro/metabolismo , Animais , Antineoplásicos/farmacologia , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células K562 , Masculino , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Microtúbulos/efeitos dos fármacos , Microtúbulos/genética , Microtúbulos/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , RNA Circular/genética , RNA Mensageiro/genética , Transdução de Sinais , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Metastasis Rev ; 43(3): 867-888, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38252399

RESUMO

Circular RNAs (circRNAs) are a member of non-coding RNAs with no ability in encoding proteins and their aberrant dysregulation is observed in cancers. Their closed-loop structure has increased their stability, and they are reliable biomarkers for cancer diagnosis. Urological cancers have been responsible for high mortality and morbidity worldwide, and developing new strategies in their treatment, especially based on gene therapy, is of importance since these malignant diseases do not respond to conventional therapies. In the current review, three important aims are followed. At the first step, the role of circRNAs in increasing or decreasing the progression of urological cancers is discussed, and the double-edged sword function of them is also highlighted. At the second step, the interaction of circRNAs with molecular targets responsible for urological cancer progression is discussed, and their impact on molecular processes such as apoptosis, autophagy, EMT, and MMPs is highlighted. Finally, the use of circRNAs as biomarkers in the diagnosis and prognosis of urological cancer patients is discussed to translate current findings in the clinic for better treatment of patients. Furthermore, since circRNAs can be transferred to tumor via exosomes and the interactions in tumor microenvironment provided by exosomes such as between macrophages and cancer cells is of importance in cancer progression, a separate section has been devoted to the role of exosomal circRNAs in urological tumors.


Assuntos
Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos , RNA Circular , Neoplasias Urológicas , Humanos , RNA Circular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/diagnóstico , Biomarcadores Tumorais/genética , Metástase Neoplásica , Animais
5.
J Cell Sci ; 136(13)2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37272356

RESUMO

Circular RNAs (circRNAs) are a class of non-coding RNA molecules that are gaining increasing attention for their roles in various pathophysiological processes. The RNA-binding protein quaking (QKI) has been identified as a regulator of circRNA formation. In this study, we investigate the role of QKI in the formation of circRNAs in the heart by performing RNA-sequencing on Qki-knockout mice. Loss of QKI resulted in the differential expression of 17% of the circRNAs in adult mouse hearts. Interestingly, the majority of the QKI-regulated circRNAs (58%) were derived from genes undergoing QKI-dependent splicing, indicating a relationship between back-splicing and linear splicing. We compared these QKI-dependent circRNAs with those regulated by RBM20, another cardiac splicing factor essential for circRNA formation. We found that QKI and RBM20 regulate the formation of a distinct, but partially overlapping set of circRNAs in the heart. Strikingly, many shared circRNAs were derived from the Ttn gene, and they were regulated in an opposite manner. Our findings indicate that QKI not only regulates alternative splicing in the heart but also the formation of circRNAs.


Assuntos
Miócitos Cardíacos , RNA Circular , Camundongos , Animais , RNA Circular/genética , RNA Circular/metabolismo , Miócitos Cardíacos/metabolismo , Processamento Alternativo/genética , Splicing de RNA , Camundongos Knockout , RNA/genética , RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo
6.
Cell Mol Life Sci ; 81(1): 276, 2024 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-38909325

RESUMO

N6-methyladenosine (m6A) is one of the most prevalent and conserved RNA modifications. It controls several biological processes, including the biogenesis and function of circular RNAs (circRNAs), which are a class of covalently closed-single stranded RNAs. Several studies have revealed that proteotoxic stress response induction could be a relevant anticancer therapy in Acute Myeloid Leukemia (AML). Furthermore, a strong molecular interaction between the m6A mRNA modification factors and the suppression of the proteotoxic stress response has emerged. Since the proteasome inhibition leading to the imbalance in protein homeostasis is strictly linked to the stress response induction, we investigated the role of Bortezomib (Btz) on m6A regulation and in particular its impact on the modulation of m6A-modified circRNAs expression. Here, we show that treating AML cells with Btz downregulated the expression of the m6A regulator WTAP at translational level, mainly because of increased oxidative stress. Indeed, Btz treatment promoted oxidative stress, with ROS generation and HMOX-1 activation and administration of the reducing agent N-acetylcysteine restored WTAP expression. Additionally, we identified m6A-modified circRNAs modulated by Btz treatment, including circHIPK3, which is implicated in protein folding and oxidative stress regulation. These results highlight the intricate molecular networks involved in oxidative and ER stress induction in AML cells following proteotoxic stress response, laying the groundwork for future therapeutic strategies targeting these pathways.


Assuntos
Adenosina , Leucemia Mieloide Aguda , Estresse Oxidativo , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Bortezomib/farmacologia , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Fatores de Processamento de RNA/metabolismo , Fatores de Processamento de RNA/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Proteínas Serina-Treonina Quinases , Peptídeos e Proteínas de Sinalização Intracelular
7.
Cell Mol Life Sci ; 81(1): 214, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38733529

RESUMO

The non-coding RNAs comprise a large part of human genome lack of capacity in encoding functional proteins. Among various members of non-coding RNAs, the circular RNAs (circRNAs) have been of importance in the pathogenesis of human diseases, especially cancer. The circRNAs have a unique closed loop structure and due to their stability, they are potential diagnostic and prognostic factors in cancer. The increasing evidences have highlighted the role of circRNAs in the modulation of proliferation and metastasis of cancer cells. On the other hand, metastasis has been responsible for up to 90% of cancer-related deaths in patients, requiring more investigation regarding the underlying mechanisms modulating this mechanism. EMT enhances metastasis and invasion of tumor cells, and can trigger resistance to therapy. The cells demonstrate dynamic changes during EMT including transformation from epithelial phenotype into mesenchymal phenotype and increase in N-cadherin and vimentin levels. The process of EMT is reversible and its reprogramming can disrupt the progression of tumor cells. The aim of current review is to understanding the interaction of circRNAs and EMT in human cancers and such interaction is beyond the regulation of cancer metastasis and can affect the response of tumor cells to chemotherapy and radiotherapy. The onco-suppressor circRNAs inhibit EMT, while the tumor-promoting circRNAs mediate EMT for acceleration of carcinogenesis. Moreover, the EMT-inducing transcription factors can be controlled by circRNAs in different human tumors.


Assuntos
Carcinogênese , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Metástase Neoplásica , Neoplasias , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Plasticidade Celular/genética , Animais , Regulação Neoplásica da Expressão Gênica
8.
Pflugers Arch ; 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39017932

RESUMO

Neuropathic pain (NPP) is a refractory pain syndrome, caused by damage or disease of the somatosensory nervous system and characterized by spontaneous pain, hyperalgesia, abnormal pain and sensory abnormality. Non-coding RNAs (ncRNAs), including microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA) and Piwi interacting RNA (piRNA), play a notable role in initiation and maintenance of NPP. In this review, we summarize the role of ncRNAs in NPP and their underlaying mechanism. Generally, ncRNAs are interacted with mRNA, protein or DNA to regulate the molecules and signals assciated with neuroinflammation, ion channels, neurotrophic factors and others, and then involved in the occurrence and development of NPP. Therefore, this review not only contributes to deepen our understanding of the pathophysiological mechanism of NPP, but also provides theoretical basis for the development of new therapy strategies for this disorder.

9.
BMC Genomics ; 25(1): 824, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223454

RESUMO

BACKGROUND: The Testis is an important reproductive organ in male mammals and the site for spermatogenesis, androgen synthesis, and secretion. Non-coding RNAs (ncRNAs) play an important regulatory role in various biological processes. However, the regulatory role of ncRNAs in the development of yak testes and spermatogenesis remains largely unclear. RESULT: In this study, we compared the expression profiles of circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in yak testicular tissue samples collected at 6 months (Y6M), 18 months (Y18M), and 4 years (Y4Y). Using RNA sequencing (RNA-Seq), we observed a significant difference in the expression patterns of ncRNAs in the samples collected at different testicular development stages. Twenty-two differentially expressed (DE) circRNAs, 69 DE miRNAs, and 64 DE mRNAs were detected in Y6M, Y18M, and Y4Y testicular samples, respectively. The results of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the source genes of DE circRNAs, predicted target genes of DE miRNAs, and DE mRNAs were specifically associated with signaling pathways and GO terms that were related to sperm synthesis, sperm vitality, and testicular development, such as cell cycle, Wnt signaling pathway, MAPK signaling pathway, GnRH signaling pathway, and spermatogenesis. The analysis of the circRNA-miRNA-mRNA network revealed that some DE ncRNAs, including miR-574, miR-449a, CDC42, and CYP11A1, among others, may be involved in testicular spermatogenesis. Concurrently, various circRNA-miRNA interaction pairs were observed. CONCLUSION: Our findings provide a database of circRNAs, miRNAs, and mRNAs expression profiles in testicular tissue of yaks at different developmental stages and a detailed understanding of the regulatory network of ncRNAs in yak testicular development and provide data that can help elucidate the molecular mechanisms underlying yak testicular development.


Assuntos
Perfilação da Expressão Gênica , MicroRNAs , RNA Circular , RNA Mensageiro , Testículo , Masculino , Animais , Testículo/metabolismo , Testículo/crescimento & desenvolvimento , RNA Circular/genética , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Bovinos/genética , Espermatogênese/genética , Análise de Sequência de RNA , Transcriptoma , Ontologia Genética , Redes Reguladoras de Genes
10.
BMC Genomics ; 25(1): 323, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561663

RESUMO

BACKGROUND: Cow milk fat is an essential indicator for evaluating and measuring milk quality and cow performance. Growing research has identified the molecular functions of circular RNAs (circRNAs) necessary for mammary gland development and lactation in mammals. METHOD: The present study analyzed circRNA expression profiling data in mammary epithelial cells (MECs) from cows with highly variable milk fat percentage (MFP) using differential expression analysis and weighted gene co-expression network analysis (WGCNA). RESULTS: A total of 309 differentially expressed circRNAs (DE-circRNAs) were identified in the high and low MFP groups. WGCNA analysis revealed that the pink module was significantly associated with MFP (r = - 0.85, P = 0.007). Parental genes of circRNAs in this module were enriched mainly in lipid metabolism-related signaling pathways, such as focal adhesion, ECM-receptor interaction, adherens junction and AMPK. Finally, six DE-circRNAs were screened from the pink module: circ_0010571, circ_0007797, circ_0002746, circ_0003052, circ_0004319, and circ_0012840. Among them, circ_0002746, circ_0003052, circ_0004319, and circ_0012840 had circular structures and were highly expressed in mammary tissues. Subcellular localization revealed that these four DE-circRNAs may play a regulatory role in the mammary glands of dairy cows, mainly as competitive endogenous RNAs (ceRNAs). Seven hub target genes (GNB1, GNG2, PLCB1, PLCG1, ATP6V0C, NDUFS4, and PIGH) were obtained by constructing the regulatory network of their ceRNAs and then analyzed by CytoHubba and MCODE plugins in Cytoscape. Functional enrichment analysis revealed that these genes are crucial and most probable ceRNA regulators in milk fat metabolism. CONCLUSIONS: Our study identified several vital circRNAs and ceRNAs affecting milk fat synthesis, providing new research ideas and a theoretical basis for cow lactation, milk quality, and breed improvement.


Assuntos
MicroRNAs , RNA Circular , Feminino , Bovinos , Animais , RNA Circular/genética , RNA Circular/metabolismo , Leite/metabolismo , RNA Endógeno Competitivo , Lactação/genética , Metabolismo dos Lipídeos/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Mamíferos/genética
11.
Mol Cancer ; 23(1): 171, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39169354

RESUMO

Circular RNAs (circRNAs) are unique noncoding RNAs that have a closed and stable loop structure generated through backsplicing. Due to their conservation, stability and tissue specificity, circRNAs can potentially be used as diagnostic indicators and therapeutic targets for certain tumors. Many studies have shown that circRNAs can act as microRNA (miRNA) sponges, and engage in interactions with proteins and translation templates to regulate gene expression and signal transduction, thereby participating in the occurrence and development of a variety of malignant tumors. Immunotherapy has revolutionized the treatment of cancer. Early researches have indicated that circRNAs are involved in regulating tumor immune microenvironment and antitumor immunity. CircRNAs may have the potential to be important targets for increasing sensitivity to immunotherapy and expanding the population of patients who benefit from cancer immunotherapy. However, few studies have investigated the correlation between circRNAs and tumor immunity. In this review, we summarize the current researches on circRNAs involved in antitumor immune regulation through different mechanisms and their potential value in increasing immunotherapy efficacy with the goal of providing new targets for cancer immunotherapy.


Assuntos
Imunoterapia , Neoplasias , RNA Circular , Microambiente Tumoral , RNA Circular/genética , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Animais , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , MicroRNAs/genética
12.
Mol Cancer ; 23(1): 59, 2024 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515149

RESUMO

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. METHODS: The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). RESULTS: Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. CONCLUSIONS: CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.


Assuntos
Neoplasias Colorretais , Indóis , MicroRNAs , Quinolinas , Humanos , Animais , Camundongos , RNA Circular/genética , Proteína Supressora de Tumor p53 , Estudos Prospectivos , MicroRNAs/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proliferação de Células/genética , Biomarcadores , Ubiquitina Tiolesterase/metabolismo , Ciclinas/metabolismo
13.
BMC Plant Biol ; 24(1): 32, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38183049

RESUMO

BACKGROUND: As a vital type of noncoding RNAs, circular RNAs (circRNAs) play important roles in plant growth and development and stress response. However, little is known about the biological roles of circRNAs in regulating the stability of male fertility restoration for cytoplasmic male sterility (CMS) conditioned by Gossypium harknessii cytoplasm (CMS-D2) cotton under high-temperature (HT) stress. RESULTS: In this study, RNA-sequencing and bioinformatics analysis were performed on pollen grains of isonuclear alloplasmic near-isogenic restorer lines NH [N(Rf1rf1)] and SH [S(Rf1rf1)] with obvious differences in fertility stability under HT stress at two environments. A total of 967 circRNAs were identified, with 250 differentially expressed under HT stress. We confirmed the back-splicing sites of eight selected circRNAs using divergent primers and Sanger sequencing. Tissue-specific expression patterns of five differentially expressed circRNAs (DECs) were also verified by RT-PCR and qRT-PCR. Functional enrichment and metabolic pathway analysis revealed that the parental genes of DECs were significantly enriched in fertility-related biological processes such as pollen tube guidance and cell wall organization, as well as the Pentose and glucuronate interconversions, Steroid biosynthesis, and N-Glycan biosynthesis pathways. Moreover, we also constructed a putative circRNA-mediated competing endogenous RNA (ceRNA) network consisting of 21 DECs, eight predicted circRNA-binding miRNAs, and their corresponding 22 mRNA targets, especially the two ceRNA modules circRNA346-miR159a-MYB33 and circRNA484-miR319e-MYB33, which might play important biological roles in regulating pollen fertility stability of cotton CMS-D2 restorer line under HT stress. CONCLUSIONS: Through systematic analysis of the abundance, characteristics and expression patterns of circRNAs, as well as the potential functions of their parent genes, our findings suggested that circRNAs and their mediated ceRNA networks acted vital biological roles in cotton pollen development, and might be also essential regulators for fertility stability of CMS-D2 restorer line under heat stress. This study will open a new door for further unlocking complex regulatory mechanisms underpinning the fertility restoration stability for CMS-D2 in cotton.


Assuntos
Gossypium , RNA Circular , Gossypium/genética , RNA Circular/genética , Citoplasma , Fertilidade/genética , RNA , Resposta ao Choque Térmico/genética
14.
Brief Bioinform ; 23(1)2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-34698333

RESUMO

Circular RNAs (circRNAs) are a large class of covalently closed RNA molecules originating by a process called back-splicing. CircRNAs are emerging as functional RNAs involved in the regulation of biological processes as well as in disease and cancer mechanisms. Current computational methods for circRNA identification from RNA-seq experiments are characterized by low discovery rates and performance dependent on the analysed data set. We developed CirComPara2 (https://github.com/egaffo/CirComPara2), a new automated computational pipeline for circRNA discovery and quantification, which consistently achieves high recall rates without losing precision by combining multiple circRNA detection methods. In our benchmark analysis, CirComPara2 outperformed state-of-the-art circRNA discovery tools and proved to be a reliable and robust method for comprehensive transcriptome characterization.


Assuntos
RNA Circular , Transcriptoma , RNA/genética , Splicing de RNA , RNA-Seq , Sequenciamento do Exoma
15.
J Transl Med ; 22(1): 694, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39075555

RESUMO

Circular RNAs (circRNAs) possess unique biological properties and distribution characteristics that enable a variety of biological functions. N6-methyladenosine (m6A), a prevalent epigenetic modification in organisms, is regulated by factors including methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). These factors play critical roles in various pathophysiological processes. There is growing evidence that m6A modifications are common within circRNAs, affecting their synthesis, translation, translocation, degradation, and stability. Additionally, circRNAs regulate biological processes that influence m6A modifications. This review explores the metabolism and functions of m6A modifications and circRNAs, their interactions, and their specific regulatory mechanisms in different tumors, offering insights into m6A-circRNA interaction in cancer.


Assuntos
Adenosina , Neoplasias , RNA Circular , Humanos , RNA Circular/metabolismo , RNA Circular/genética , Neoplasias/genética , Neoplasias/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais
16.
J Transl Med ; 22(1): 704, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39080693

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have been implicated in the development and progression of gastric cancer (GC). However, it remains unclear whether dysregulated circRNA affects immune escape and the efficacy of immunotherapy in GC. Our aim is to investigate the molecular mechanism of circRNA affecting GC immunotherapy and identify effective molecular therapeutic targets. METHODS: The differential expression profile of circRNAs was established through circRNA sequencing, comparing three paired GC tissues with their adjacent non-cancerous gastric tissues. The expression level of circRHBDD1 in GC tissues was then assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The biological characteristics of circRHBDD1 were verified through a series of experiments, including agarose gel electrophoresis assays, RNase R treatment, and actinomycin D experiments. The prognostic value of circRHBDD1 in GC was evaluated by conducting both univariate and multivariate survival analyses. Furthermore, loss- and gain-of-function approaches were utilized to investigate the impact of circRHBDD1 on GC immune escape. RNA-sequencing, immunoprecipitation, flow cytometry, and methylated RNA immunoprecipitation (meRIP) analysis were performed to elucidate the underlying molecular mechanisms. RESULTS: We discovered that circRHBDD1 exhibited remarkably high expression levels in GC tissues and cell lines. Notably, the high expression of circRHBDD1 was significantly correlated with poor overall survival and disease-free survival among GC patients. Both in vitro and in vivo experiments revealed that circRHBDD1 upregulated the expression of PD-L1 and impeded the infiltration of CD8+ T cells. Further, we found that circRHBDD1 binds to IGF2BP2, disrupting the interaction between E3 ligase TRIM25 and IGF2BP2, and ultimately inhibiting IGF2BP2 ubiquitination and degradation. Intriguingly, IGF2BP2 enhances PD-L1 mRNA stability through m6A modification. Additionally, we developed Poly (lactide-co-glycolic acid) (PLGA)-Polyethylene glycol (PEG)-based nanoparticles loaded with circRHBDD1 siRNA. In vivo experiments validated that the combination of PLGA-PEG(si-circRHBDD1) and anti-PD-1 offers a safe and efficacious nano-drug regimen for cancer immunotherapy. CONCLUSION: Our results demonstrated that circRHBDD1 promoted GC immune escape by upregulating the expression of PD-L1 and reprogramming T cell-mediated immune response. Inhibition of circRHBDD1 expression could potentially enhance the response of GC patients to immunotherapy, thus improving treatment outcomes. Additionally, the development of a nanodrug delivery system provides a feasible approach for future clinical applications.


Assuntos
Antígeno B7-H1 , RNA Circular , Proteínas de Ligação a RNA , Transdução de Sinais , Neoplasias Gástricas , Evasão Tumoral , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Prognóstico , RNA Circular/genética , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia
17.
Crit Rev Microbiol ; : 1-15, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38967384

RESUMO

The gut microbiota features an abundance of diverse microorganisms and represents an important component of human physiology and metabolic homeostasis, indicating their roles in a wide array of physiological and pathological processes in the host. Maintaining balance in the gut microbiota is critical for normal functionality as microbial dysbiosis can lead to the occurrence and development of diseases through various mechanisms. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are non-coding RNAs that perform important regulatory functions for many processes. Furthermore, the gut microbiota and lncRNAs/circRNAs are known to interact in a range of both physiological and pathological activities. In this article, we review existing research relevant to the interaction between the gut microbiota and lncRNAs/circRNAs and investigate the role of their crosstalk in the pathogenesis of different diseases. Studies have shown that, the gut microbiota can target lncRNAs ENO1-IT1, BFAL1, and LINC00152 to regulate colorectal cancer development via various signaling pathways. In addition, the gut microbiota can influence mental diseases and lung tumor metastasis by modulating circRNAs such as circNF1-419, circ_0001239, circHIPK2 and mmu_circ_0000730. These findings provide a theoretical basis for disease prevention and treatment and suggest that gut microbiota-lncRNA/circRNA crosstalk has high clinical value.

18.
Rev Endocr Metab Disord ; 25(2): 399-420, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38157150

RESUMO

White adipose tissue (WAT) serves as the primary site for energy storage and endocrine regulation in mammals, while brown adipose tissue (BAT) is specialized for thermogenesis and energy expenditure. The conversion of white adipocytes to brown-like fat cells, known as browning, has emerged as a promising therapeutic strategy for reversing obesity and its associated co-morbidities. Noncoding RNAs (ncRNAs) are a class of transcripts that do not encode proteins but exert regulatory functions on gene expression at various levels. Recent studies have shed light on the involvement of ncRNAs in adipose tissue development, differentiation, and function. In this review, we aim to summarize the current understanding of ncRNAs in adipose biology, with a focus on their role and intricate mechanisms in WAT browning. Also, we discuss the potential applications and challenges of ncRNA-based therapies for overweight and its metabolic disorders, so as to combat the obesity epidemic in the future.


Assuntos
Tecido Adiposo Branco , Obesidade , Animais , Humanos , Tecido Adiposo Branco/metabolismo , Obesidade/genética , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Adipócitos/metabolismo , Adiposidade , RNA não Traduzido/genética , Termogênese/genética , Metabolismo Energético/genética , Mamíferos
19.
J Biomed Sci ; 31(1): 63, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877495

RESUMO

Within the intricate tapestry of molecular research, noncoding RNAs (ncRNAs) were historically overshadowed by a pervasive presumption of their inability to encode proteins or peptides. However, groundbreaking revelations have challenged this notion, unveiling select ncRNAs that surprisingly encode peptides specifically those nearing a succinct 100 amino acids. At the forefront of this epiphany stand lncRNAs and circRNAs, distinctively characterized by their embedded small open reading frames (sORFs). Increasing evidence has revealed different functions and mechanisms of peptides/proteins encoded by ncRNAs in cancer, including promotion or inhibition of cancer cell proliferation, cellular metabolism (glucose metabolism and lipid metabolism), and promotion or concerted metastasis of cancer cells. The discoveries not only accentuate the depth of ncRNA functionality but also open novel avenues for oncological research and therapeutic innovations. The main difficulties in the study of these ncRNA-derived peptides hinge crucially on precise peptide detection and sORFs identification. Here, we illuminate cutting-edge methodologies, essential instrumentation, and dedicated databases tailored for unearthing sORFs and peptides. In addition, we also conclude the potential of clinical applications in cancer therapy.


Assuntos
Neoplasias , Peptídeos , RNA não Traduzido , Humanos , Neoplasias/genética , Neoplasias/metabolismo , RNA não Traduzido/genética , Peptídeos/genética , Peptídeos/metabolismo , Fases de Leitura Aberta
20.
EMBO Rep ; 23(5): e54117, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35239998

RESUMO

Non-coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact the development and progression of multiple diseases. Herpesviruses, including Kaposi's sarcoma-associated herpesvirus, are adept at utilising ncRNAs, encoding their own as well as dysregulating host ncRNAs to modulate virus gene expression and the host response to infection. Research has mainly focused on unidirectional ncRNA-mediated regulation of target protein-coding transcripts; however, we identify a novel host ncRNA regulatory network essential for KSHV lytic replication in B cells. KSHV-mediated upregulation of the host cell circRNA, circHIPK3, is a key component of this network, functioning as a competing endogenous RNA of miR-30c, leading to increased levels of the miR-30c target, DLL4. Dysregulation of this network highlights a novel mechanism of cell cycle control during KSHV lytic replication in B cells. Importantly, disruption at any point within this novel ncRNA regulatory network has a detrimental effect on KSHV lytic replication, highlighting the essential nature of this network and potential for therapeutic intervention.


Assuntos
Herpesvirus Humano 8 , MicroRNAs , Linfócitos B , Herpesvirus Humano 8/genética , MicroRNAs/genética , RNA Circular/genética , Regulação para Cima
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