Function of noncoding RNA in epigenetic and transcriptional regulation

非编码RNA在表观遗传和转录调控中的功能

• 批准号: RGPIN-2015-04658
• 负责人: He, Housheng
• 金额: $ 2.55万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708106
• 关键词: Function; noncoding; RNA; epigenetic; transcriptional

Epigenetic regulators including readers, writers, erasers of histone modifications and DNA methylation, have been recognized to play key roles in transcriptional regulation. Decipher how epigenetic regulators manipulate the transcriptional networks is critical to understand the mechanism of transcriptional regulation. Transcriptional network consists the functional relationship between all the driving transcription factors (TF) and their target genes in a biological process. The bottleneck in transcriptional network construction is the lacking of efficient method to simultaneously capture all driven factors and their global binding sites. Although ChIP-seq is powerful in capture transcription factor binding sites genome-widely, the application of this technology requires the knowledge of the transcription factors of interest beforehand, and the availability of ChIP grade antibodies. In addition, the ChIP-seq experiment needs to be conducted one transcription factor at a time, making it inefficient in network construction that usually involves multiple transcription factors. More cost effective approaches to determine multiple transcription factors binding simultaneously are needed for transcriptional network study. Epigenetic regulator interacts with chromatin to perform its condition specific function. As an enzyme, epigenetic regulator lacks sequence-specific recognition. How does epigenetic regulator recognize specific genomic loci for epigenetic regulation is a long-standing question. Noncoding RNA (ncRNA), particularly long noncoding RNA (lncRNA), can interact with epigenetic regulator through its three dimensional structure, can also interact with DNA through RNA-DNA triplex-structure, thus has the potential to function as a guiding factor for epigenetic regulator. It was recently discovered that an lncRNA named HOTAIR, which can interact coordinately with polycomb repressive complex 2 and H3K4 demethylase LSD1 to target chromatin repression and gene silencing. We hypothesize that ncRNAs interact with epigenetic regulators to control transcriptional networks in biological systems. The short-term objective of this proposal is to develop approach to investigate epigenetic regulator transcriptional networks. The long-term objective is to identify interaction between epigenetic regulator and ncRNA and elucidate their function in transcriptional regulation. The novel approach will be developed can be widely adopted to construct transcriptional network. The transcriptional network of LSD1 and its associated noncoding RNAs will help to address the long-standing question of how epigenetic regulator is recruited to specific genomic loci.

表观遗传调控因子，包括读者、编写者、组蛋白修饰的擦除器和DNA甲基化，已被认为在转录调控中发挥关键作用。破译表观遗传调控如何操纵转录网络是理解转录调控机制的关键。转录网络是指生物过程中所有驱动转录因子(Tf)及其靶基因之间的功能关系。构建转录网络的瓶颈是缺乏有效的方法来同时捕获所有驱动因子及其全局结合位点。虽然CHIP-SEQ在全基因组范围内捕获转录因子结合位点的能力很强，但这项技术的应用需要事先了解感兴趣的转录因子，并获得芯片级抗体。此外，CHIP-SEQ实验需要一次进行一个转录因子，这使得它在通常涉及多个转录因子的网络构建中效率低下。转录网络研究需要更经济有效的方法来同时确定多个转录因子的结合。 表观遗传调节因子与染色质相互作用，发挥其特定条件下的功能。作为一种酶，表观遗传调控因子缺乏序列特异性识别。表观遗传调控因子如何识别特定的基因组位点进行表观遗传调控是一个长期存在的问题。非编码RNA(NcRNA)，尤其是长非编码RNA(LncRNA)可以通过其三维结构与表观遗传调控因子相互作用，也可以通过RNA-DNA三链结构与DNA相互作用，因此有可能成为表观遗传调控的指导因子。最近发现了一种名为HOTAIR的lncRNA，它可以与多梳抑制复合体2和H3K4去甲基酶LSD1协同作用，靶向染色质抑制和基因沉默。 我们假设，ncRNAs与表观遗传调节因子相互作用，控制生物系统中的转录网络。这项建议的短期目标是开发一种方法来研究表观遗传调节转录网络。长期的目标是确定表观遗传调控因子和ncRNA之间的相互作用，并阐明它们在转录调控中的功能。LSD1及其相关的非编码RNA的转录网络将有助于解决如何将表观遗传调节因子招募到特定基因组座位这一长期存在的问题。