长链非编码RNA在神经系统中的研究进展

长链非编码RNA (long noncoding RNA, lncRNA)是多种复杂有机体转录组中最主要的一类转录本. lncRNA在各种生物之间序列保守性差、表达量普遍比较低.与编码基因相比,lncRNA有相似的启动子区域以及剪切位点,具有较好的细胞和组织特异性分布,尤其在神经系统中具有较为丰富的表达,提示它们在神经系统中具有不可忽视的作用.本文围绕近几年lncRNA在神经系统方面的最新研究成果,总结了lncRNA对中枢和外周神经系统发育以及对神经系统功能等方面的调控作用及机制.同时展望了有关lncRNA研究的新理念和新技术及对未来神经科学研究的推动作用.     

Adaptor proteins in long noncoding RNA biology

Long noncoding RNAs (lncRNAs) are a heterogeneous class of noncoding RNAs that have gained increasing attention due to their vital roles in the regulation of diverse cellular processes. Because lncRNAs are generally expressed at low levels, are poorly conserved, and can act via diverse mechanisms, investigating the molecular mechanisms by which lncRNAs act is challenging. Similar to mRNAs, lncRNAs bind to RNA-binding proteins (RBPs) and in some cases, have been shown to regulate the activity of the RBP they bind to. Furthermore, recent studies have shown that some lncRNAs directly bind to a specific RBP that, in turn, forms a complex with other proteins that mediate the effects of the lncRNA. We termed such RBPs as adaptor proteins because they function as adaptors to recruit other proteins that indirectly associate with the lncRNA. Here, we discuss the emerging roles of adaptor proteins in lncRNA function and propose mechanistic scenarios and strategies to identify adaptor proteins that could play vital roles in the biology of a lncRNA. This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen.     

与眼部疾病相关的长链非编码RNA的研究进展

长链非编码RNA(long non-coding RNA,LncRNA)是一类长度大于200个核苷酸不具备编码蛋白质功能的转录子,在表观遗传、转录或转录后水平调节基因的表达,维持细胞稳态。研究表明多种LncRNA的表达失衡在肿瘤细胞的增殖、转移、干细胞的全能性、免疫细胞的发育及应答过程中发挥重要。新近的研究显示许多LncRNAs特异表达与眼部疾病发生密切相关。本文主要对目前报道的与眼部常见疾病如翼状胬肉、白内障、青光眼、糖尿病视网膜病变、眼部肿瘤等差异表达LncRNAs的功能和作用机制进行了综述,以期为LncRNAs作为眼部疾病的生物学标记和潜在治疗靶点的的应用提供参考资料。     

调控肌肉生长发育的lncRNAs

长链非编码RNA（long non-coding RNA, lncRNA）是存在于真核生物体内的一种长度大于200 nt主要由RNA聚合酶Ⅱ转录而来的RNAs,且不具有编码蛋白质能力。作为机体基因调控网络的重要调节因子,lncRNA在X染色体沉默、脂肪代谢、细胞生长发育等方面发挥重要作用。近期研究结果表明,lncRNA通过介导表观遗传、转录水平和转录后水平调控等方式,参与骨骼肌的生长发育以及分化过程的调节,包括调控肌源性干细胞和成肌细胞的增殖、分化和肌管的融合等进程,从而影响肌肉的生长发育。本文概述了lncRNA的分类与生物学功能,归纳了lncRNA的作用机制,重点介绍参与骨骼肌生长发育调控的lncRNAs,分析目前lncRNA研究面临的机遇及挑战,展望未来研究的热点与方向,以期为lncRNA在肌肉生长调控方面开展深入研究提供参考。     

Rise of the RNA Machines: Exploring the Structure of Long Non-Coding RNAs

Novel, profound and unexpected roles of long non-coding RNAs (lncRNAs) are emerging in critical aspects of gene regulation. Thousands of lncRNAs have been recently discovered in a wide range of mammalian systems, related to development, epigenetics, cancer, brain function and hereditary disease. The structural biology of these lncRNAs presents a brave new RNA world, which may contain a diverse zoo of new architectures and mechanisms. While structural studies of lncRNAs are in their infancy, we describe existing structural data for lncRNAs, as well as crystallographic studies of other RNA machines and their implications for lncRNAs. We also discuss the importance of dynamics in RNA machine mechanism. Determining commonalities between lncRNA systems will help elucidate the evolution and mechanistic role of lncRNAs in disease, creating a structural framework necessary to pursue lncRNA-based therapeutics.     

小麦长链非编码RNA的预测及功能分析

生物体有部分基因被转录成RNA,但是不编码相应蛋白质,称为长链非编码RNA(lncRNA)。它们参与基因的表观调控,这一过程对动物、植物的生长发育都有重要作用,但是,目前植物中发现和研究的lncRNA较少。为了研究lncRNA在植物中的功能,本研究建立了基于小麦全长cDNA的lncRNA识别程序。从6162条小麦全长cDNA中发现了231条lncRNAs,并从中鉴定出两个新miRNAs,这表明lncRNAs可以通过形成miRNAs前体基因形成其功能。此外,通过序列富集分析,我们从小麦lncRNAs中鉴定出三个保守的调控元件,结果显示小麦lncRNAs可能通过和其它蛋白质或DNA等分子作用,进而参与小麦生长、发育等过程的调控,这些结果对进一步研究植物体内的lncRNA的功能和作用机制具有重要意义。     

与眼部疾病相关的长链非编码RNA的研究进展

长链非编码RNA(long non-coding RNA,LncRNA)是一类长度大于200个核苷酸不具备编码蛋白质功能的转录子,在表观遗传、转录或转录后水平调节基因的表达,维持细胞稳态。研究表明多种LncRNA的表达失衡在肿瘤细胞的增殖、转移、干细胞的全能性、免疫细胞的发育及应答过程中发挥重要。新近的研究显示许多LncRNAs特异表达与眼部疾病发生密切相关。本文主要对目前报道的与眼部常见疾病如翼状胬肉、白内障、青光眼、糖尿病视网膜病变、眼部肿瘤等差异表达LncRNAs的功能和作用机制进行了综述,以期为LncRNAs作为眼部疾病的生物学标记和潜在治疗靶点的的应用提供参考资料。     

LncRNAs and immunity: watchdogs for host pathogen interactions

Immune responses combat various infectious agents by inducing inflammatory responses, antimicrobial pathways and adaptive immunity. The polygenic responses to these external stimuli are temporally and coordinately regulated. Specific lncRNAs are induced to modulate innate and adaptive immune responses which can function through various target interactions like RNA-DNA, RNA-RNA, and RNA-protein interaction and hence affect the immunogenic regulation at various stages of gene expression. LncRNA are found to be present in various immune cells like monocytes, macrophages, dendritic cells, neutrophils, T cells and B cells. They have been shown to be involved in many biological processes, including the regulation of the expression of genes, the dosage compensation and genomics imprinting, but the knowledge how lncRNAs are regulated and how they alter cell differentiation/function is still obscure. Further dysregulation of lncRNA has been seen in many diseases, but as yet very less research has been carried out to understand the role of lncRNAs in regulation during host-pathogens interactions. In this review, we summarize the functional developments and mechanism of action of lncRNAs, in immunity and defense of host against pathogens.     

Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs

The recent discovery that the human and other mammalian genomes produce thousands of long non-coding RNAs (lncRNAs) raises many fascinating questions. These mRNA-like molecules, which lack significant protein-coding capacity, have been implicated in a wide range of biological functions through diverse and as yet poorly understood molecular mechanisms. Despite some recent insights into how lncRNAs function in such diverse cellular processes as regulation of gene expression and assembly of cellular structures, by and large, the key questions regarding lncRNA mechanisms remain to be answered. In this review, we discuss recent advances in understanding the biology of lncRNAs and propose avenues of investigation that may lead to fundamental new insights into their functions and mechanisms of action. Finally, as numerous lncRNAs are dysregulated in human diseases and disorders, we also discuss potential roles for these molecules in human health.     

LncRNA Gm2044 highly expresses in spermatocyte and inhibits Utf1 translation by interacting with Utf1 mRNA

Spermatogenesis is a process which includes the following phases: spermatogonial stem cell proliferation and differentiation, spermatogonia, spermatocyte, spermatid and mature sperm. Spermatogenic failure is the important factor resulting in male infertility. Recent studies showed that long noncoding RNA (lncRNA) have been found to be involved in the regulation of male reproduction. However, lncRNA associated with spermatogenesis and their mechanisms of action are unclear. The aim of this study is to explore the role and molecular mechanism of lncRNA in spermatogenesis. LncRNA microarray of germ cells and bioinformatic analysis showed lncRNA Gm2044 may play potential roles in spermatogenesis. The expression level of RNA and protein were analyzed by RT-qPCR and western blotting, respectively. The interaction of lncRNA with mRNA was detected by RNA pull down and cellular proliferation was measured using CCK-8 reagent. Testis-enriched lncRNA Gm2044 is abundant in mouse spermatocytes. Gm2044 can suppress the translation of adjacent spermatogenesis-related gene Utf1 by interacting with Utf1 mRNA. Furthermore, the proliferation of mouse spermatogonia GC-1 cell line and spermatocyte GC-2 cell line was inhibited by Gm2044. CONCLUSION: LncRNA Gm2044 was identified to inhibit Utf1 mRNA translation and play important roles in spermatogenesis.     

Identification of mitochondrial function‐associated lncRNAs in septic mice myocardium

The present study aimed to analyze long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in septic mice heart and to identify potential lncRNAs and mRNAs that be responsible for cardiac mitochondrial dysfunction during sepsis. Mice were treated with 10 mg/kg of lipopolysaccharides to induce sepsis. LncRNAs and mRNAs expression were evaluated by using lncRNA and mRNA microarray or real‐time polymerase chain reaction technique. LncRNA‐mRNA coexpression network assay, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. The results showed that 1275 lncRNAs were differentially expressed in septic myocardium compared with those in the control group. A total of 2769 mRNAs were dysregulated in septic mice heart, most of which are mainly related to the process of inflammation, mitochondrial metabolism, oxidative stress, and apoptosis. Coexpression network analysis showed that 14 lncRNAs were highly correlated with 11 mitochondria‐related differentially expressed mRNA. Among all lncRNAs and their cis‐acting mRNAs, 41 lncRNAs‐mRNA pairs (such as NONMMUG004378 and Apaf1 gene) were enriched in GO terms and KEGG pathways. In summary, we gained some specific lncRNAs and their potential target mRNAs that might be involved in mitochondrial dysfunction in septic myocardium. These findings provide a panoramic view of lncRNA and might allow developing new treatment strategies for sepsis.     

LncRNA FAF attenuates hypoxia/ischaemia‐induced pyroptosis via the miR‐185‐5p/PAK2 axis in cardiomyocytes

Pyroptosis is associated with various cardiovascular diseases. Increasing evidence suggests that long noncoding RNAs (lncRNAs) have been implicated in gene regulation, but how lncRNAs participate in the regulation of pyroptosis in the heart remains largely unknown. In this study, we aimed to explore the antipyroptotic effects of lncRNA FGF9‐associated factor (FAF) in acute myocardial infarction (AMI). The expression patterns of lncRNA FAF, miR‐185‐5p and P21 activated kinase 2 (PAK2) were detected in hypoxia/ischaemia‐induced cardiomyocytes. Hoechst 33342/PI staining, lactate dehydrogenase (LDH) release assay, immunofluorescence and Western blotting were conducted to assay cell pyroptosis. The interaction between lncRNA FAF, miR‐185‐5p and PAK2 was verified by bioinformatics analysis, small RNA sequencing luciferase reporter assay and qRT‐PCR. The expression of LncRNA FAF was downregulated in hypoxic cardiomyocytes and myocardial tissues. Overexpression of lncRNA FAF could attenuate cardiomyocyte pyroptosis, improve cell viability and reduce infarct size during the procession of AMI. Moreover, lncRNA FAF was confirmed as a sponge of miR‐185‐5p and promoted PAK2 expression in cardiomyocytes. Collectively, our findings reveal a novel lncRNA FAF/miR‐185‐5p/PAK2 axis as a crucial regulator in cardiomyocyte pyroptosis, which might be a potential therapeutic target of AMI.     

lncRNA作为竞争性内源RNA在非小细胞肺癌中的作用

长链非编码RNA(long non-coding RNA,lncRNA)参与肿瘤的多种生理、病理进程.研究表明,lncRNA可通过与微小RNA (microRNA, mi RNA)反应元件相互作用,并与其他RNA分子形成竞争性内源RNA (competing endogenous RNA,ceRNA)的调控网络,参与基因的表达调控.lncRNA以ceRNA方式参与非小细胞肺癌(non-small cell lung cancer,NSCLC)的发生发展过程,为揭示NSCLC的分子机理开拓了新的思路,也为NSCLC的治疗提供新的靶点.本文在课题组前期发现NSCLC相关ceRNA基础上,主要讨论lncRNA作为ceRNA在NSCLC中高表达、低表达及治疗相关方面的作用.