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长链非编码RNA每个月都有几十篇高分文章见刊，机制也是多种多样，咱们号上一期总结了5篇高分文章的高分套路，有些同学意犹未尽，今天小能手再给大家来5篇，定期给大家更新高分文章的机制研究套路，也方便大家找思路写本子做实验。 1. Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter. Nucleic Acids Res11.5611区. 2019 Apr 8 不用多说，MALAT1这个最知名的lncRNA了，从我第一次接触非编码RNA的概念时，就知道MALAT1了。 分子机制：这里面有一个正反馈回路机制。作者通过RNA-seq发现被HIV-1病毒感染的CD4+ T免疫细胞中MALAT1上调表达，接下来的细胞实验发现，过表达以及敲减（CRISPR技术）后证明，MALAT1起到促进HIV-1感染细胞的病毒的复制，以及相关HIV-1 LTR先关驱动基因的表达。机制上：MALAT1通过与PRC2蛋白复合物的写作，从HIV-1 LTR启动子区域上解离了甲基化启动蛋白EZH2，从而去除H3K27的组蛋白甲基化修饰。而HIV-1的活跃，又可促进MALAT1的表达，形成正反馈回路机制。 基金中正反馈回路相关的课题 摘要：In HIV-1 infected CD4+ T cells, we performed RNA-Sequencing (RNA-Seq) analysis and discovered an up-regulation of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1). we found that MALAT1 promoted HIV-1 transcription and infection, as its knockdown by CRISPR/Cas9 markedly reduced the HIV-1 long terminal repeat (LTR)-driven gene transcription and viral replication. Mechanistically, through an association with chromatin modulator polycomb repressive complex 2 (PRC2), MALAT1 detached the core component enhancer of zeste homolog 2 (EZH2) from binding with HIV-1 LTR promoter, and thus removed PRC2 complex-mediated methylation of histone H3 on lysine 27 (H3K27me3) and relieved epigenetic silencing of HIV-1 transcription. Moreover, the reactivation of HIV-1 stimulated with latency reversal agents (LRAs) induced MALAT1 expression in latently infected cells. （最知名的lncRNA，MALAT-1的发现：2003年，Ji等从初期非小细胞肺癌患者的肿瘤细胞中筛选出数个差异表达基因，其中包括含一个与肺癌转移和预后相关的未知转录物，采用RACE法扩增到一个长约940nt的片段，经检索比对，该片段定位于人染色体11q13，属于长约8.7kb的a基因。Ji等根据其与NSCLC发生发展的关系，将a基因转录物重命名为肺癌转移相关转录本1（MALAT-1），后来也被称作NEAT2。MALAT-1缺乏有意义的开放性编码框，在体外无法翻译蛋白质，属长链非编码RNA（lncRNA）。MALAT-1是第一个与肺癌疾病相关联的长链非编码RNA。10多年前发现关于MALAT-1的大量数据积累，包括MALAT-1与其他癌症细胞或疾病的关联、对其生物合成的见解、与其他细胞的相互作用及分子机制等。） 2.The lncRNA Neat1 promotes activation of inflammasomes in macrophages. Nat Commun12.3532区. 2019 Apr 2 分子机制：已知炎症小体在机体固有免疫发挥重要作用。本文中lncRNA NEAT1可在巨噬细胞中激活数种炎症小体，包括NLRP3, NLRC4, AIM2炎症小体。NEAT1可潜伏在paraspeckle小体中，在受到炎症小体刺激信号时，从paraspeckle小体中释放解离，游离到细胞质中，NEAT1通过特异性吸附提升caspase-1的稳定性，进而增加了IL-1β的释放，促进细胞焦亡的发生。 （paraspeckle：细胞生物学中，paraspeckle小体指细胞核染色质间隙中的一种不规则亚结构区域，大小约0.2-1微米。这种结构首先在Hela细胞中被发现，大约在每个细胞核中存在10-30个。后续研究表明，这种结构存在于所有的人类原代细胞，转化细胞以及组织切片中。） 摘要：The inflammasome has an essential function in innate immune, responding to a wide variety of stimuli. Here we show that the lncRNA Neat1 promotes the activation of several inflammasomes. Neat1 associates with the NLRP3, NLRC4, and AIM2 inflammasomes in mouse macrophages to enhance their assembly and subsequent pro-caspase-1 processing. Neat1 also stabilizes the mature caspase-1 to promote interleukin-1β production and pyroptosis. Upon stimulation with inflammasome-activating signals, Neat1, which normally resides in the paraspeckles, disassociates from these nuclear bodies and translocates to the cytoplasm to modulate inflammasome activation using above mechanism. Neat1 is also up-regulated under hypoxic conditions in a HIF-2α-dependent manner, mediating the effect of hypoxia on inflammasomes. Moreover, in the mouse models of peritonitis and pneumonia, Neat1 deficiency significantly reduces inflammatory responses. 3.LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition. Cell Res15.3931区1. 2019 Apr 分子机制：已知PTEN是抑癌基因，其具有双特异性-磷酸酯酶的活性，但是从未有报道对其双特异性磷酸酯酶的功能有报道。K27介导的PTEN的66和68赖氨酸位点的多泛素化修饰，可使其从磷酸肌醇/络氨酸磷酸酯酶活性切换成为丝氨酸/络氨酸磷酸酯酶活性。高糖, TGF-β, CTGF, SHH, 以及 IL-6诱导一个叫做lncRNA MEX3C的上调表达，其可直接介导K27介导的PTEN的66和68赖氨酸位点的多泛素化修饰，促进了PTEN发挥ser/tyr磷酸酯酶活性。而使得TWIST1, SNAI1以及YAP1的ser氨酸残基以及tyr氨酸残基去磷酸化，从而使得这些EMT相关marker积累，诱导EMT的潜在发生。 （PTEN基因，编码由403个氨基酸组成的蛋白质，具有磷酸酯酶的活性。PTEN蛋白可通过拮抗酪氨酸激酶等磷酸化酶的活性而抑制肿瘤的发生发展。实验表明，将野生型PTEN基因转染到该基因异常的胶质母细胞瘤后，肿瘤细胞的生长、侵袭能力受到明显抑制，发现其对肿瘤细胞的酪氨酸激酶FAK（focal adhesion kinase ）的活性有明显的抑制作用。此外，PTEN蛋白还可通过特异性地使IP3的第三位磷酸去磷酸化而间接地抑制胰岛素诱导的磷酸肌醇-3激酶的活性，而IP3是胰岛素调节细胞生长信号通路中的重要的第二信使，可见PTEN蛋白在细胞生长信号通路中起重要作用。） 摘要：Despite the structural conservation of PTEN with dual-specificity phosphatases, there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase activity. Here, we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase activity. Mechanistically, high glucose, TGF-β, CTGF, SHH, and IL-6 induce the expression of a long non-coding RNA, GAEA (Glucose Aroused for EMT Activation), which associates with an RNA-binding E3 ligase, MEX3C, and enhances its enzymatic activity, leading to the K27-linked polyubiquitination of PTEN. The MEX3C-catalyzed PTENK27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity. With this altered enzymatic activity, PTENK27-polyUb dephosphorylates the phosphoserine/threonine residues of TWIST1, SNAI1, and YAP1, leading to accumulation of these master regulators of EMT. Animals with genetic inhibition of PTENK27-polyUb, by a single nucleotide mutation generated using CRISPR/Cas9 (PtenK80R/K80R), exhibit inhibition of EMT markers during mammary gland morphogenesis in pregnancy/lactation and during cutaneous wound healing processes. Our findings illustrate an unexpected paradigm in which the lncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development. 4.A Transforming Growth Factor-β and H19 Signaling Axis in Tumor-Initiating Hepatocytes That Regulates Hepatic Carcinogenesis. Hepatology14.0791区1. 2019 Apr 分子机制：肝癌进展中TGF-β信号通路发挥着不同阶段的功能。作者把TGF-βR2失活后，体内外实验发现肝癌细胞TIC（tumor-initiating cell）细胞增殖情况更加疯狂，且小鼠体内有更多的转移灶。机制上，TGF-βR2失活后，一个lncRNA H19上调表达了至少5倍，而TGF-β处理后H19的表达下降了，进一步的机制表明SOX2转录因子调控者H19的表达，调控着TGF-β-H19的调控信号。 （肿瘤干细胞（cancer stem cell, CSC）也称为肿瘤起源细胞（tumor-initiating cell），是从肿瘤组织中分离或鉴定的少数细胞，具有无限的自我更新和诱导肿瘤发生的能力，是肿瘤产生的种子细胞。） 摘要：Functions of transforming growth factor-β (TGF-β) in the liver vary depending on specific cell types and their temporal response to TGF-β during different stages of hepatocarcinogenesis (HCG). Through analysis of tumor tissues from hepatocellular carcinoma (HCC) patients, we were able to cluster hepatic epithelial cell-derived TGF-β gene signatures in association with distinct clinical prognoses. RNA sequencing (RNA-seq) analysis identified H19 as one of the most up-regulated long noncoding RNA (lncRNA) in association with Tgfbr2 inactivation in TICs. Tgfbr2 inactivation by Ad-Cre led to a 5-fold increase of H19 expression in TICs. Accordingly, TGF-β treatment reduced H19 expression. We observed that forced overexpression of Sox2 in TICs increased transcription of H19, whereas knockdown of Sox2 decreased it. Furthermore, depletion of H19 reduced the progenitor property of TICs in vitro and decreased their tumorigenic potential in vivo. Finally, we observed a low level of H19 mRNA expression in human HCC tissues from patients with the epithelial TGF-β gene signature in association with favorable prognosis. Conclusion: Our findings describe a TGF-β and H19 signaling axis by Sox2 in TICs that importantly regulates HCG. 5.LncIRS1 controls muscle atrophy via sponging miR-15 family to activate IGF1-PI3K/AKT pathway. J Cachexia Sarcopenia Muscle12.5111区. 2019 Ap 分子机制：作者研究的是肌肉萎缩课题，其首先用生信的方式构建了ceRNA网络。通过实验验证了lncIRS1可同时吸附家族miRNA如miR-15a, miR-15b-5p以及 miR-15c-5p，从而促进 IRS1基因的表达。而IRS1基因是IGF1 receptor的下游靶基因，同时lncIRS1还可以促进AKT蛋白的磷酸化，激活PI3K-AKT信号通路。 摘要：We constructed a myogenesis-associated lncRNA-miRNA-gene network and identified a novel ceRNA lncRNA named lncIRS1 that is specifically enriched in skeletal muscle. LncIRS1 could regulate myoblast proliferation and differentiation in vitro, and muscle mass and mean muscle fibre in vivo. LncIRS1 increases gradually during myogenic differentiation. Mechanistically, lncIRS1 acts as a ceRNA for miR-15a, miR-15b-5p, and miR-15c-5p to regulate IRS1 expression, which is the downstream of the IGF1 receptor. Overexpression of lncIRS1 not only increased the protein abundance of IRS1 but also promoted phosphorylation level of AKT (p-AKT) a central component of insulin-like growth factor-1 pathway. Furthermore, lncIRS1 regulates the expression of atrophy-related genes and can rescue muscle atrophy.
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来自： Hobart_joe > 《lncRNA》
