PRC2 Recruitment to Target Genes Via Non-Coding RNAs

描述(由申请人提供)：多梳抑制复合体2(PRC2)向靶基因的招募一直是染色质领域非常感兴趣的话题。尽管许多实验室做出了努力，但这种对发育至关重要的复合体如何实现靶标特异性尚不完全清楚。近年来引起人们极大关注的一个想法是，发现非编码RNA(NcRNAs)可以在染色质上的特定位置引导PRC2。最终在其他几个附件和核心组件中发现了RNA结合区(RBR)，这增加了ncRNAs可能介导PRC2招募的可能性。在这个提案中，我将研究其中一个ncRNAs的功能，即MEG3，它被发现与辅助蛋白JARID2结合。这一建议的生物学意义在于观察到MEG3 ncRNA与基因簇的异常沉默有关，这些基因簇在诱导多能干细胞(IPSCs)分化中起重要作用。因此，由于这种效应，IPSC衍生疗法的真正潜力受到了阻碍。这一提议的发现将有助于深入了解RNA和蛋白质之间的复杂相互作用，并提供一种PRC2招募到靶基因的机制。

DESCRIPTION (provided by applicant): Recruitment of the Polycomb Repressive Complex 2 (PRC2) to target genes has been the topic of a lot of interest in the chromatin field. Despite the efforts by many labs, it is not entirely clear how such a developmentally essential complex achieves target specificity. One idea that has attracted much attention in recent years was the discovery that non-coding RNAs (ncRNAs) can direct PRC2 at specific sites on chromatin. The eventual identification of RNA binding regions (RBRs) in several other accessory and core components raised the possibility that ncRNAs may mediate PRC2 recruitment. In this proposal, I will investigate the function of one of these ncRNAs, namely MEG3, which was found to bind to the accessory protein JARID2. The biological relevance of this proposal is the observation that MEG3 ncRNA is associated with aberrant silencing of gene clusters that are important in differentiation of induced pluripotency stem cells (iPSCs). Thus, the true potential of iPSC-derived therapies has hampered due to this effect. The findings from this proposal will shed insight into the complex interactions between RNA and protein, and provide a mechanism of PRC2 recruitment to target genes.