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.
Findings of this proposal will help understand the regulation of gene expression in the context of the establishment and/or maintenance of cellular identity and have wide implications on fields such as regenerative medicine. A major problem with induced pluripotency stem cells (iPSCs), which prevents their therapeutic utility, is the aberrant silencin of genes clusters. A clear understanding of the molecular mechanisms of repression is needed to pave the way to improved cell based therapies for the treatment of diseases.
|Gao, Zhonghua; Lee, Pedro; Stafford, James M et al. (2014) An AUTS2-Polycomb complex activates gene expression in the CNS. Nature 516:349-54|