长链非编码RNA与表观遗传调控

近年来,表观遗传学(epigenetics)备受关注.表观遗传调控的方式主要包括DNA甲基化、组蛋白修饰和染色质重塑等.ENCODE计划及随后的研究发现,人类基因组中仅有很小一部分DNA序列负责编码蛋白质,而其余大部分被转录为非编码RNA(non-codingRNA,ncRNA).其中长链非编码RNA(long non-codingRNA,lncRNA)是一类长度大于200nt并且缺乏蛋白质编码能力的RNA分子.越来越多的研究表明,lncRNAs能够通过表观遗传调控、转录调控以及转录后调控等多个层面调节基因的表达,从而参与细胞增殖、分化和凋亡等多种生物学过程.本文将着重综述lncRNAs在表观遗传调控中的作用及其最新的研究进展.     

Long non-coding RNA UCA1 promotes breast tumor growth by suppression of p27 (Kip1)

Functional genomics studies have led to the discovery of a large amount of non-coding RNAs from the human genome; among them are long non-coding RNAs (lncRNAs). Emerging evidence indicates that lncRNAs could have a critical role in the regulation of cellular processes such as cell growth and apoptosis as well as cancer progression and metastasis. As master gene regulators, lncRNAs are capable of forming lncRNA–protein (ribonucleoprotein) complexes to regulate a large number of genes. For example, lincRNA-RoR suppresses p53 in response to DNA damage through interaction with heterogeneous nuclear ribonucleoprotein I (hnRNP I). The present study demonstrates that hnRNP I can also form a functional ribonucleoprotein complex with lncRNA urothelial carcinoma-associated 1 (UCA1) and increase the UCA1 stability. Of interest, the phosphorylated form of hnRNP I, predominantly in the cytoplasm, is responsible for the interaction with UCA1. Moreover, although hnRNP I enhances the translation of p27 (Kip1) through interaction with the 5′-untranslated region (5′-UTR) of p27 mRNAs, the interaction of UCA1 with hnRNP I suppresses the p27 protein level by competitive inhibition. In support of this finding, UCA1 has an oncogenic role in breast cancer both in vitro and in vivo. Finally, we show a negative correlation between p27 and UCA in the breast tumor cancer tissue microarray. Together, our results suggest an important role of UCA1 in breast cancer.     

长链非编码RNA相关表观遗传修饰在癌症中的进展*

长链非编码RNA(lncRNA)是一类转录本长度大于200 nt的RNA分子,编码蛋白质的功能有限,但其功能多样且复杂。已有研究报道lncRNA与肿瘤的发展进程密切相关,lncRNA可以通过不同方式参与细胞内生物学进程的调控,是潜在的癌症调节因子,其中,调节表观遗传修饰水平是其影响癌症进程的主要手段;癌症发病过程中细胞内存在着不同程度的表观遗传修饰,其主要为包括甲基化、乙酰化、磷酸化、糖基化、泛素化等修饰方式在内的DNA修饰、RNA修饰以及蛋白质的翻译后修饰,在癌症的不同阶段其修饰的异常程度不同,从而影响肿瘤发生的生物学进程。研究表明,lncRNA可以通过自身修饰或参与其他生物大分子的表观遗传修饰进程参与癌症的发生发展。因此,回顾了lncRNA所参与的表观遗传修饰形式和lncRNA在表观遗传修饰方面所起到的作用,并概述了lncRNA通过影响表观遗传修饰水平从而调控癌症进程的方法。旨在总结癌症细胞内表观遗传修饰方面所涉及lncRNA的研究进展,为癌症诊断和治疗提供潜在的靶标和生物学标志物。     

长链非编码RNA表征及其在结直肠癌发生发展中的作用和临床意义

长非编码RNA（long non-coding RNAs, lncRNAs）是一类转录本长度大于200个核苷酸,不具有蛋白质编码功能的非编码RNA（non-coding RNA, ncRNA）。人类基因组中,ncRNA基因占比超过90%,数量远大于蛋白质编码基因。作为生物大分子,lncRNA具有特定的初级和高级结构,在基因表达调控等生物学进程中发挥着特有的功能。lncRNA数量多,结构各异,因此鉴定和表征新的lncRNA,探索其结构和功能,是当前基因研究领域的热点之一。在临床疾病机制研究中,大量结果表明,lncRNA与临床疾病发生发展,特别是肿瘤的发生发展具有密切的相关性。伴随着后基因组学时代基因鉴定和功能探索方法的不断进步,探索lncRNA在疾病发生中的功能及表达变化,深入解锁lncRNA在疾病发生中涉及的分子机制,将为疾病早期预防、诊断和预后提供有效参考。基于以上的研究大背景,本文对lncRNA的定义、基因鉴定的策略和方法,高级结构检测及其对应的生物学功能,以及lncRNA的分类进行了阐述;另一方面,基于lncRNA与肿瘤发生发展的密切关系,本文以经典抑癌基因p53为切入点,对多种p53相关的lncRNA在结直肠癌（colorectal cancer, CRC）发生发展中的作用进行了归纳小结,阐述了lncRNA在结直肠癌中的表达变化、涉及的分子互作机制和信号通路,对其作为分子标志物在临床中的应用潜力进行了评估。我们乐观地认为,作为生物分子标志物,lncRNA将为包括癌症在内的疾病治疗提供全新、精准和个性化的分子靶点。     

Long Non-coding RNA Derived from lncRNA–mRNA Co-expression Networks Modulates the Locust Phase Change

Long non-coding RNAs (lncRNAs) regulate various biological processes ranging from gene expression to animal behavior. Although protein-coding genes, microRNAs, and neuropeptides play important roles in the regulation of phenotypic plasticity in migratory locust, empirical studies on the function of lncRNAs in this process remain limited. Here, we applied high-throughput RNA-seq to compare the expression patterns of lncRNAs and mRNAs in the time course of locust phase change. We found that lncRNAs responded more rapidly at the early stages of phase transition. Functional annotations demonstrated that early changed lncRNAs employed different pathways in isolation and crowding phases to cope with changes in the population density. Two overlapping hub lncRNA loci in the crowding and isolation networks were screened for functional verification. One of them, LNC1010057, was validated as a potential regulator of locust phase change. This work offers insights into the molecular mechanism underlying locust phase change and expands the scope of lncRNA functions in animal behavior.     

长链非编码RNA的微RNA海绵作用与呼吸系统疾病

长链非编码RNA（long non-coding RNAs, lncRNAs）是一类由长度大于200个核苷酸组成的长链非编码序列。lncRNAs具有较长的序列,使得lncRNAs具有复杂的二级及三级结构,这也是lncRNAs结合DNA、RNA和蛋白质及其行使复杂功能的结构基础。MicroRNA（miRNAs)是长度在19到25个核苷酸之间的非编码单链RNA分子,是目前研究最多的小分子非编码RNA。而lncRNAs通过结合或者螯合miRNA来调节miRNA丰度,发挥lncRNA的“海绵”作用,从而调控一系列的病理生理过程。lncRNAs及miRNA在呼吸系统疾病的发生、发展、治疗和预后起重要作用。本文就lncRNAs及其“海绵”作用对呼吸系统疾病的影响及可能的机制进行综述。     

长非编码RNA THOR在肿瘤中的作用

长非编码RNA（long non-coding RNA,lncRNA）是一类长度超过200 nt并且缺乏蛋白质编码潜能的RNA分子。最初lncRNA被认为是由RNA聚合酶Ⅱ转录的副产物,且无生物学功能。随着转录组测序技术的发展,大规模的lncRNA被鉴定出来。越来越多的证据表明,lncRNA参与多种生物学过程,包括基因印记、基因组重排、染色质修饰、细胞周期调控、转录、剪接、mRNA降解和翻译。lncRNA异常表达与人类多种疾病相关,尤其是增生性疾病,包括胃癌、肝癌和直肠癌等。其中,睾丸相关的高度保守的致癌长非编码RNA（testis-associated highly-conserved oncogenic long non-coding RNA,THOR）是一种非常保守的非编码RNA,在睾丸中特异性表达,并广泛存在于人的多种肿瘤组织中,如肝癌、胃癌、鼻咽癌、肾细胞癌、骨肉瘤、视网膜母细胞瘤、黑色素瘤、非小细胞肺癌和舌鳞状细胞癌中,在其发生和发展过程中发挥重要作用。在鼻咽癌、肾细胞癌、骨肉瘤、黑色素瘤、非小细胞肺癌和舌鳞状细胞癌中,THOR主要通过与胰岛素样生长因子2 mRNA结合蛋白1（insulin-like growth factor 2 mRNA-binding protein 1,IGF2BP1）相互作用,促进肿瘤细胞的增殖。在肝癌中,THOR分别通过PTEN/AKT和β-联蛋白信号促进癌细胞的增殖和肝肿瘤干细胞的扩增。在胃癌和骨肉瘤中,THOR主要通过提高SOX9的表达增强癌细胞的干性。在视网膜母细胞瘤中,THOR主要通过提高c-myc的表达促进癌细胞增殖。在鼻咽癌中,THOR主要通过提高YAP的表达增强癌细胞的干性。     

长非编码RNA THOR在肿瘤中的作用

长非编码RNA（long non-coding RNA,lncRNA）是一类长度超过200 nt并且缺乏蛋白质编码潜能的RNA分子。最初lncRNA被认为是由RNA聚合酶Ⅱ转录的副产物,且无生物学功能。随着转录组测序技术的发展,大规模的lncRNA被鉴定出来。越来越多的证据表明,lncRNA参与多种生物学过程,包括基因印记、基因组重排、染色质修饰、细胞周期调控、转录、剪接、mRNA降解和翻译。lncRNA异常表达与人类多种疾病相关,尤其是增生性疾病,包括胃癌、肝癌和直肠癌等。其中,睾丸相关的高度保守的致癌长非编码RNA（testis-associated highly-conserved oncogenic long non-coding RNA,THOR）是一种非常保守的非编码RNA,在睾丸中特异性表达,并广泛存在于人的多种肿瘤组织中,如肝癌、胃癌、鼻咽癌、肾细胞癌、骨肉瘤、视网膜母细胞瘤、黑色素瘤、非小细胞肺癌和舌鳞状细胞癌中,在其发生和发展过程中发挥重要作用。在鼻咽癌、肾细胞癌、骨肉瘤、黑色素瘤、非小细胞肺癌和舌鳞状细胞癌中,THOR主要通过与胰岛素样生长因子2 mRNA结合蛋白1（insulin-like growth factor 2 mRNA-binding protein 1,IGF2BP1）相互作用,促进肿瘤细胞的增殖。在肝癌中,THOR分别通过PTEN/AKT和β-联蛋白信号促进癌细胞的增殖和肝肿瘤干细胞的扩增。在胃癌和骨肉瘤中,THOR主要通过提高SOX9的表达增强癌细胞的干性。在视网膜母细胞瘤中,THOR主要通过提高c-myc的表达促进癌细胞增殖。在鼻咽癌中,THOR主要通过提高YAP的表达增强癌细胞的干性。     

LncRNA与肝脏糖脂代谢的研究进展

长链非编码RNA (Long non-coding RNA,lncRNA)因参与多个层级上的生物进程而成为当下生命科学领域的研究热点。LncRNA可以与DNA、RNA和蛋白质等生物分子结合,并进一步影响靶基因的转录、翻译以及翻译后修饰等过程,从而发挥在细胞生理代谢过程中的调控作用。目前研究显示,lncRNA通过多种途径在肝脏代谢中发挥重要作用。文中以lncRNA的功能及其与肝脏能量代谢和相关疾病的关系为着眼点,阐述了lncRNA发挥作用的机制以及未来的研究前景。     

DNA methylation and gene expression profiles characterize epigenetic regulation of lncRNAs in colon adenocarcinoma

The long noncoding RNAs (lncRNAs) are associated with tumorigenesis and progression of cancer. While DNA methylation is a common epigenetic regulator of gene expression, the methylation of lncRNAs was rarely studied. To address this gap, we integrated DNA methylation and RNA-seq data to characterize the landscape of lncRNA methylation in colon adenocarcinoma (COAD). We collected and analyzed the lncRNA expression and methylation data from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia to identify the epigenetically regulated lncRNAs. We further investigated the biological and clinical relevance of the identified lncRNAs via bioinformatics analysis. We identified 20 epigenetically upregulated lncRNAs in COAD, including several well-studied lncRNAs whose methylation regulation were poorly investigated, such as PVT1 and UCA1. We also revealed several novel tumor-associated lncRNAs in COAD, including GATA2-As1 and CYTOR. Next, we explored their biology function using gene set enrichment analysis and competitive endogenous RNA analysis. We characterized the methylation landscape of lncRNA in COAD and identified 20 epigenetically upregulated lncRNAs. Our findings will shed new light on the epigenetic regulation of lncRNA expression by DNA methylation.     

An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells

Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer. The potential role of lncRNAs and their epigenetic regulation in response to platinum treatment are largely unknown. We analyzed four paired cisplatin-sensitive/resistant non-small cell lung cancer and ovarian cancer cell lines. The epigenetic landscape of overlapping and cis-acting lncRNAs was determined by combining human microarray data on 30,586 lncRNAs and 20,109 protein coding mRNAs with whole-genome bisulfite sequencing. Selected candidate lncRNAs were further characterized by PCR, gene-ontology analysis, and targeted bisulfite sequencing. Differential expression in response to therapy was observed more frequently in cis-acting than in overlapping lncRNAs (78% vs. 22%, fold change ≥1.5), while significantly altered methylation profiles were more commonly associated with overlapping lncRNAs (29% vs. 8%; P value <0.001). Moreover, overlapping lncRNAs contain more CpG islands (CGIs) (25% vs. 17%) and the majority of CGI-containing overlapping lncRNAs share these CGIs with their associated coding genes (84%). The differences in expression between sensitive and resistant cell lines were replicated in 87% of the selected candidates (P<0.05), while our bioinformatics approach identifying differential methylation was confirmed in all of the selected lncRNAs (100%). Five lncRNAs under epigenetic regulation appear to be involved in cisplatin resistance (AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, and AF198444). These novel findings provide new insights into epigenetic mechanisms and acquired resistance to cisplatin that highlight specific lncRNAs, some with unknown function, that may signal strategies in epigenetic therapies.