长非编码RNA

人类基因组序列的约5%～10%被稳定转录,蛋白质编码基因仅约占1%,其余4%～9%的序列虽能转录,但转录物功能尚不明确。尽管如此,已确证在非蛋白质编码转录物中,含有具备调节功能的非编码RNA(noncoding RNA,ncRNA)。与具有调节功能的短链非编码RNA[如微RNA(microRNA)、小干扰RNA(siRNA),、Piwi-RNA]相比,长非编码RNA(long noncoding RNA,lncRNA)在数量上占大多数。lncRNA通过多种方式产生,以多种途径调节靶基因表达,参与调控生物体生长、发育、衰老、死亡等过程;lncRNA功能异常往往导致疾病发生。本文综述了lncRNA的起源、分类、作用分子机制及lncRNA异常与疾病的相关性等内容,旨在充分了解这一重要新型调控分子。     

Modulation of cancer cell signaling by long noncoding RNAs

Cellular signaling pathways play a very important role in almost all molecular processes in the cell, and are generally composed of a complex set of cascades in which enzymes and proteins play a key role. These signaling pathways include different types of cellular signaling classified based on their receptors and effector proteins such as enzyme-linked receptors, cytokine receptors, and G-protein-coupled receptors each of which is subdivided into different classes. Signaling pathways are tightly controlled by different mechanisms mostly thorough inhibiting/activating their receptors or effector proteins. In the last two decades, our knowledge of molecular biology has changed dramatically and today we know that more than 85% of the human genome expresses noncoding RNAs most of which are crucial in the cellular and molecular mechanisms of cells. One of these noncoding RNAs are long noncoding RNAs (lncRNA) containing more than 200 nucleotides. LncRNAs participate in the progression of cancer growth through several mechanism including signaling pathways. In this review, we summarize some of the most important of lncRNAs and their effect on important signaling pathways.     

长链非编码RNA研究进展

基因组计划研究表明, 在组成人类基因组的30亿个碱基对中, 仅有1.5%的核酸序列用于蛋白质编码, 其余98.5%的基因组为非蛋白质编码序列。这些序列曾被认为是在进化过程中累积的“垃圾序列”而未予以关注, 但在随后启动的ENCODE研究计划中却发现, 75%的基因组序列能够被转录成RNA, 其中近74%的转录产物为非编码RNA(Non-coding RNA, ncRNA)。在非编码RNA中, 绝大多数转录本的长度大于200个碱基, 这些“长链非编码RNA(Long non-coding RNA, lncRNA)”能够在转录及转录后水平上调节蛋白编码基因的表达, 从而广泛地参与包括细胞分化、个体发育在内的重要生命过程, 其异常表达还与多种人类重大疾病的发生密切相关。文章综述了长链非编码RNA的发现、分类、表达、作用机制以及其在个体发育和人类疾病中的作用。     

Rapid senescence‐like response after acute injury

Cellular senescence is a state of irreversible growth arrest. Short‐term programmed senescence such as in embryonic development and slowly progressing senescence as in aging are both well described. However, acute senescence in living organisms is not well understood. We hypothesized that hemorrhagic shock injury (HI) caused by whole body hypoxia and nutrient deprivation, resulting in organ dysfunction due to severe blood loss, could lead to acute senescence in vivo. Our experiments, for the first time, demonstrate a rapidly emerged, senolytics‐responsive, senescence‐like response in the rat liver in less than five hr following hemorrhagic shock. We conclude that the senescence, or pseudosenescence, observed is necessary to maintain tissue homeostasis following the injury.     

长非编码RNA的作用机制及在肿瘤发生发展中的意义

功能基因组学的飞速发展将越来越多的目光引向了对非编码转录产物功能的研究。在人的转录组中,存在着一类长度大于200nt,但并不具备编码蛋白质功能的基因转录产物,即长非编码RNA(long noncoding RNA,lncRNA)。相比于小分子RNA,它们仍是目前基因组转录产物中较为陌生的部分。在整个基因组转录产物中,lncRNA所占的比例远远超过编码RNA所占的比例。不同于编码RNA,lncRNA的保守性要差得多,然而在其分子内部,却含有较为保守的局部区段,且其表达具有时空特异性,这些现象都提示了lncRNA具有重要的生理生化功能。越来越多的研究表明,lncRNA在基因表达调控方面发挥着十分重要的作用,与物种进化、胚胎发育、物质代谢以及肿瘤发生等都有着紧密的联系,其功能的深入研究将使目前对细胞的结构网络和调控网络的认识带来革命性的变化,具有不可估量的科学和临床价值。该文将着重讨论lncRNA在不同层面上对基因表达的调控机制以及在肿瘤发生发展中的意义。     

非编码长链RNA与基因表达调控

近年来,在小鼠全长cDNA文库大规模测序中发现一类新的转录物——非编码长链RNA(long noncoding RNA,lncRNA),引起了科学界的关注.lncRNA长度大于200个核苷酸,无蛋白质编码功能,在真核细胞基因组中被普遍转录.lncRNA种类繁多,数量庞大,占哺乳动物基因组转录物的绝大部分.相对于研究较多的非编码小RNA,lncRNA的功能目前尚不完全清楚.但越来越多的研究发现,lncRNA在多个水平调控基因的表达,在胚胎发育、物种进化、细胞分化和某些疾病如神经退行性疾病及肿瘤的发生过程中起着重要作用.本文在简要介绍lncRNA基本概念的基础上,结合当前研究成果,就lncRNA在转录水平、转录后水平和表观遗传水平调控基因表达的机制作一综述.     

长链非编码RNA的作用机制及其研究方法

长链非编码RNA(Long non-coding RNA, lncRNA)通过多种机制发挥其生物学功能, 这些机制包括基因印记、染色质重塑、细胞周期调控、剪接调控、mRNA降解和翻译调控等。lncRNA通过这些作用机制在不同水平进行基因表达调控。在研究lncRNA功能的过程中, 研究方法的建立和应用起着非常重要的作用。目前用于lncRNA研究的主要方法有：微阵列、转录组测序、Northern印迹、实时荧光定量逆转录-聚合酶链反应、荧光原位杂交、RNA干扰和RNA结合蛋白免疫沉淀等。文章着重介绍了3种前沿方法, 即：在线快速预测RNA与蛋白质相互作用的catRAPID、RNA纯化的染色质分离(Chromatin isolation by RNA purification, ChIRP)以及非编码RNA沉默与定位分析技术(Combined knockdown and localization analysis of non-coding RNAs, c-KLAN)。     

Unusual semi‐extractability as a hallmark of nuclear body‐associated architectural noncoding RNAs

NEAT1_2 long noncoding RNA (lncRNA) is the molecular scaffold of paraspeckle nuclear bodies. Here, we report an improved RNA extraction method: extensive needle shearing or heating of cell lysate in RNA extraction reagent improved NEAT1_2 extraction by 20‐fold (a property we term “semi‐extractability”), whereas using a conventional method NEAT1_2 was trapped in the protein phase. The improved extraction method enabled us to estimate that approximately 50 NEAT1_2 molecules are present in a single paraspeckle. Another architectural lncRNA, IGS16, also exhibited similar semi‐extractability. A comparison of RNA‐seq data from needle‐sheared and control samples revealed the existence of multiple semi‐extractable RNAs, many of which were localized in subnuclear granule‐like structures. The semi‐extractability of NEAT1_2 correlated with its association with paraspeckle proteins and required the prion‐like domain of the RNA‐binding protein FUS. This observation suggests that tenacious RNA–protein and protein–protein interactions, which drive nuclear body formation, are responsible for semi‐extractability. Our findings provide a foundation for the discovery of the architectural RNAs that constitute nuclear bodies.     

IL‐1α cleavage by inflammatory caspases of the noncanonical inflammasome controls the senescence‐associated secretory phenotype

Interleukin‐1 alpha (IL‐1α) is a powerful cytokine that modulates immunity, and requires canonical cleavage by calpain for full activity. Mature IL‐1α is produced after inflammasome activation and during cell senescence, but the protease cleaving IL‐1α in these contexts is unknown. We show IL‐1α is activated by caspase‐5 or caspase‐11 cleavage at a conserved site. Caspase‐5 drives cleaved IL‐1α release after human macrophage inflammasome activation, while IL‐1α secretion from murine macrophages only requires caspase‐11, with IL‐1β release needing caspase‐11 and caspase‐1. Importantly, senescent human cells require caspase‐5 for the IL‐1α‐dependent senescence‐associated secretory phenotype (SASP) in vitro, while senescent mouse hepatocytes need caspase‐11 for the SASP‐driven immune surveillance of senescent cells in vivo. Together, we identify IL‐1α as a novel substrate of noncanonical inflammatory caspases and finally provide a mechanism for how IL‐1α is activated during senescence. Thus, targeting caspase‐5 may reduce inflammation and limit the deleterious effects of accumulated senescent cells during disease and Aging.     

Four long noncoding RNAs as potential prognostic biomarkers for hepatocellular carcinoma

The study aimed to identify the long noncoding RNAs (lncRNAs) biomarkers for occurrence and prognosis of patients with hepatocellular carcinoma (HCC), and simultaneously to investigate the potential role of lncRNAs in the oncogenesis of HCC. The lncRNAs expression data and the corresponding clinical information of HCC samples were extracted from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes and lncRNAs were identified and the correlation networks were constructed. In this study, we identified 212 differentially expressed lncRNAs and 7,577 differentially expressed genes between liver HCC tumor tissues and normal tissue samples. And then, combining with clinical information, a total of 11 lncRNAs and 162 genes as HCC biomarkers were identified by comprehensive bioinformatics analysis. Further, through coexpress network analysis, we confirmed four lncRNAs (lncRNA_ANKRD10.IT1, lncRNA_CTD.2583A14.8, lncRNA_RP11.404P21.3, and lncRNA_RP11.488L18.10), which can serve as prognostic biomarkers for HCC. The four lncRNAs identified in this study may serve as a potential therapy target for HCC.     

Calmodulin‐like skin protein suppresses the increase in senescence‐associated β‐galactosidase induced by hydrogen peroxide or ultraviolet irradiation in keratinocytes

Calmodulin‐like skin protein (CLSP) is a secreted peptide that is produced by skin keratinocytes and some related epithelial cells. It has previously been shown that CLSP is recruited via the bloodstream into the central nervous system where it likely exerts a neuroprotective effect against toxicity related to Alzheimer's disease (AD) by binding to the heterotrimeric humanin receptor and activating intracellular survival signaling. However, it remains to be elucidated whether secreted CLSP shows a protective effect in the skin tissues. In the current study, using primary keratinocytes treated with hydrogen peroxide (H₂O₂) or exposed to ultraviolet (UV) irradiation as senescence models of keratinocytes, we addressed whether CLSP affects senescence in skin keratinocytes. We found that CLSP expression was upregulated by H₂O₂ or UV in keratinocytes. Furthermore, co‐incubation with recombinant CLSP reduced the increase in senescence‐associated β‐galactosidase‐positivity in keratinocytes that were induced by H₂O₂ or UV. These results suggest that CLSP may function as a senescence‐suppressing factor in keratinocytes.