全校师生：

我校定于2019年5月11日举办研究生灵犀学术殿堂——胡继繁教授报告会，现将有关事项通知如下：

1.报告会简介

报告人：胡继繁教授

时间：2019年5月11日（星期六）上午11:30

地点：西北工业大学国际会议中心第五会议室

报告题目：Functional characterization of lncRNAs as epigenetic messengers in cancers by combining RAT-seq and CRIST-seq assays

内容简介：A significant portion of the human genome encodes nonprotein-coding genes that are transcribed extensively as long noncoding RNAs (lncRNAs). It is now clear that these lncNRAs function as critical epigenetic players of the regulatory complexes essential for the development and progression of cancers. Currently, most of studies have been focused on their “sponge” role in sequestering functional miRNAs in the cytosol. However, little is known about the role of a large number of nuclear lncRNAs, either enriched in chromatin complexes or localized to specific sub-nuclear compartments. We proposed to use combined RAT-seq and CRIST-seq to characterize nuclear lncRNAs as epigenetic message carriers in cancers.

Friend leukemia virus integration 1 (FLI1), an ETS transcription factor family member, acts as an oncogenic driver both in hematological malignancies and in solid tumors. However, regulatory factors that activate this proto-oncogene in tumors remain unknown. Using CRIST-Seq, we mapped RNA components in the FLI1 promoter chromatin complex and identified two circular RNAs, consisting of FLI1 exons 4-2-3 and exons 5-2-3-4, referred to as FECRs (FLI1 exonic circular RNAs). FECR1 enhanced tumor invasiveness of MDA-MB231 breast cancer cells. Mechanistically, we found that FECR1 utilized a positive feedback mechanism to activate the oncogenic FLI1 by inducing DNA hypomethylation in CpG islands of the promoter. FECR1 bound to the FLI1 promoter in cis and recruited TET1, a demethylase that is actively involved in DNA demethylation. Using RAT-seq, we found that FECR1 bound to and downregulated DNMT1 in trans, a methyltransferase that is essential for the maintenance of DNA methylation. These data suggest that oncogenic FLI1 drives tumor metastasis not only through the canonical oncoprotein pathway, but also by using epigenetic mechanisms mediated by its exonic circular RNA. FECR1 circular RNA acts as an upstream epigenetic regulator to control breast tumor growth by coordinating DNA methylating and demethylating enzymes in cis and in trans.

LncND5 is a mitochondrial genome-encoded lncRNA that is transcribed in antisense to the ND5 gene. In lung adenocarcinoma cells, we surprisingly found that this mitochondrial lncRNA was abnormally shuffled to the nucleus. Using RAT-seq, we profiled its genome-wide target interactome and identified the intron 3 enhancer of tumor suppressor BACH2 as a critical nuclear target of lncND5. Knockdown ofLncND5 increased BACH2 expression, and inhibited cell proliferation, invasion, and adhesion. Six CpG islands in the BACH2 promoter were epigenetically regulated by lncND5 in lung adenocarcinoma cells. These data suggest an aberrant shuffling of mitochondrial-encoded lncND5 to the nucleus, where it binds to the enhancer of tumor-suppressor BACH2 gene, and epigenetically regulates BACH2 expression.

Collectively, the combined RAT-seq and CRIST-seq may be used as a useful approach to map functional lncRNAs in cancer development and progression.

人类基因组的很大一部分编码非蛋白编码基因，这些基因被广泛地转录为长非编码RNA (lncRNA)。现在很清楚的是，这些lncNRAs作为调控复合物的关键表观遗传学参与者，对癌症的发展和进展至关重要。目前，大多数研究都集中在它们在细胞溶胶中隔离功能miRNA的“海绵”作用上。然而，我们对大量核lncRNA的作用知之甚少，它们要么富含染色质复合物，要么定位于特定的亚核区。我们建议使用RAT-seq和CRIST-seq结合来描述核lncRNA作为癌症中的表观遗传信息载体。

Friend leukemia virus integration 1 (FLI1)是ETS转录因子家族成员之一，在血液病恶性肿瘤和实体肿瘤中均作为致癌驱动因子。然而，在肿瘤中激活这种原癌基因的调控因素仍不清楚。利用CRIST-Seq，我们绘制了FLI1启动子染色质复合物中的RNA组分，并鉴定了两个环状RNA，分别由FLI1外显子4-2-3和外显子5-2-3-4组成，称为FECRs (FLI1外显子环状RNA)。FECR1增强了MDA-MB231乳腺癌细胞的侵袭性。机制上，我们发现FECR1利用正反馈机制通过诱导启动子CpG岛的DNA低甲基化来激活致癌的FLI1。FECR1与顺式FLI1启动子结合并募集TET1，这是一种积极参与DNA去甲基化的脱甲基酶。利用RAT-seq，我们发现FECR1与反式DNMT1结合并下调。反式甲基转移酶对维持DNA甲基化至关重要。这些数据表明，致癌的FLI1不仅通过典型的癌蛋白通路，而且通过其外显子环状RNA介导的表观遗传机制驱动肿瘤转移。FECR1环状RNA是一种上游表观遗传调节剂，通过在顺式和反式中协调DNA甲基化和去甲基化酶来控制乳腺肿瘤的生长。LncND5是线粒体基因组编码的lncRNA，其以反义ND5基因转录。在肺腺癌细胞中，我们惊奇地发现这种线粒体lncRNA异常转移到细胞核。使用RAT-seq，我们分析了其全基因组目标相互作用组，并鉴定了肿瘤抑制因子BACH2的内含子3增强子作为lncND5的关键核靶点。敲除LncND5增加BACH2表达，并抑制细胞增殖、侵袭和粘附。BACH2启动子中的六个CpG岛由肺腺癌细胞中的lncND5进行表观遗传学调节。这些数据表明线粒体编码的lncND5异常转移至细胞核，在细胞核中与肿瘤抑制基因BACH2基因的增强子结合，并在表观遗传学上调控BACH2表达。

总的来说，RAT-seq和CRIST-seq的结合可以用作在癌症发展和进展中绘制功能性lncRNA的一种有用方法。

2.欢迎各学院师生前来听报告。报告会期间请关闭手机或将手机调至静音模式。

党委学生工作部

生命学院

2019年4月29日 

报告人简介

胡继繁，教授，博士生导师，吉林大学“唐敖庆学者”，吉林省优秀归国人才。主要研究方向为肿瘤干细胞、表观遗传学和长链非编码RNA相关基础研究。在美国斯坦福大学肿瘤和干细胞表观遗传学实验室任职期间，先后以P.I.和Co-P.I.的身份完成美国国立卫生研究所/美国国立癌症研究所（NIH/NCI）和美国国防部（US Department of Defense, DoD）的科研课题三项，2012年成功获得关于长链非编码RNA的国家自然科学基金面上项目一项，2014年成功获得关于长链非编码RNA的国家自然科学基金重点项目一项。以第一作者和通讯作者在包括Science、cell stem cell、Nat Communication、Nucleic Acids Research等国际顶尖杂志上发表SCI论文80余篇，被引次数超过5000次。