在早期发育和癌变过程中发挥功能的极长基因间非编码RNA调控网络的鉴定

In the past decade, long non-coding RNAs have gained significant prominence due to their involvement in virtually every biological process and disease. While some lncRNAs have been shown to regulate other genes, most of lncRNAs in human cells remain uncharacterized, potentially harboring a multitude of important regulatory molecules with yet un-characterized regulatory networks. We have recently discovered a widespread class of very long intergenic non-coding (vlinc)RNAs in human cells. A sub-group of these transcripts appears to function in early embryonic development and cancer. This offers a tantalizing new connection between pluripotent and malignant states and could add significant novel insights into the biogenesis of this disease. We propose a research program where we would (1) identify vlincRNA regulatory networks in pluripotent and cancer cells based on genomics approaches and (2) uncover how networks get reprogrammed during the malignant transformation. We will then perform (3) extensive validation and refinement of these networks using Systems Biology approaches. Finally, based on this information, we will develop (4) a computer model that would predict targets of other vlincRNAs and lncRNAs in general. This would represent a major significant contribution to our understanding of molecular regulatory mechanisms in normal development and their aberration during disease and to the field of lncRNA research in general.

长链非编码RNAs几乎参与到所有的生理与疾病发展过程，在过去十年内受到了高度的关注。目前虽有部分长链非编码RNAs已被证实调控其他基因，绝大多数人类细胞中的长链非编码RNAs的作用仍然未知，其中潜藏大量重要的调控分子以及未知的调控网络。我们已经发现一类极长基因间非编码RNAs，其具有与早期胚胎发育以及癌症相关的功能性作用，这预示着细胞多能性和癌变之间的潜在关联性，为细胞癌变的理论研究提供新的思路。本课题拟通过基因组学分析并建立胚胎干细胞以及癌细胞中，由极长基因间非编码RNAs与靶标基因所组成的调控网络，并用系统生物学方法进行验证及完善。并基于极长基因间非编码RNAs和靶标的对应关系，开发非编码RNA靶标预测的计算机模型。本课题对正常发育细胞与癌变过程中细胞的分子调控机制的阐明以及长片段非编码RNA领域的研究发展具有重要而深远的意义。

长链非编码RNA（lncRNA）参与了几乎所有的生理过程，而其中大多数的生物学功能及机制仍未知。本项目着重研究一类lncRNA——极长基因间非编码RNA（vlincRNA）。证明了vlincRNA对癌细胞响应药物（尤其是基因毒性药物）作用时的细胞存活具有重要功能。并发现vlincRNA参与DNA损伤反应。为深入阐明vlinRNA和DNA损伤的联系，团队开发了一种在核苷酸分辨率下的全基因组DNA单链断裂检测方法，可对细胞“断裂组”研究提供新思路。团队还基于共表达分析构建了407个vlincRNA的调控网络，并通过vlincRNA-染色质相互作用检测及vlincRNA靶向敲低进行验证。团队发现vlincRNA可调控多种顺式和反式基因，这些基因在与RNA代谢和加工、细胞周期及发育等有关的特定功能中富集。本项目中建立的vlincRNA功能注释分析和验证策略可被应用于其他类型lncRNA的功能注释。