A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation

Long noncoding RNAs (lncRNAs) participate in various biological processes such as apoptosis. The function of lncRNAs is closely correlated with their localization within the cell. While regulatory potential of many lncRNAs has been revealed at specific subcellular location, the biological significance of discrete distribution of an lncRNA in different cellular compartments remains largely unexplored. Here, we identified an lncRNA antisense to the pro-apoptotic gene PYCARD, named PYCARD-AS1, which exhibits a dual nuclear and cytoplasmic distribution and is required for the PYCARD silencing in breast cancer cells. The PYCARD-regulated apoptosis is controlled by PYCARD-AS1; moreover, PYCARD-AS1 regulates apoptosis in a PYCARD-dependent manner, indicating that PYCARD is a critical downstream target of PYCARD-AS1. Mechanistically, PYCARD-AS1 can localize to the PYCARD promoter, where it facilitates DNA methylation and H3K9me2 modification by recruiting the chromatin-suppressor proteins DNMT1 and G9a. Moreover, PYCARD-AS1 and PYCARD mRNA can interact with each other via their 5 overlapping region, leading to inhibition of ribosome assembly in the cytoplasm for PYCARD translation. This study reveals a mechanism whereby an lncRNA works at different cellular compartments to regulate the pro-apoptotic gene PYCARD at both the epigenetic and translational levels, contributing to the PYCARD-regulated apoptosis, and also sheds new light on the role of discretely distributed lncRNAs in diverse biological processes. Author summary As the reveal of tens of thousands of long noncoding RNAs (lncRNAs) from mammalian genomes, there is increasing interest to understand how these transcripts function in physiological and pathological processes. The regulatory potential of many lncRNAs has been revealed at specific subcellular location. Nevertheless, many lncRNAs are discretely distributed in different cellular compartments, and the related biological significance remains largely unclear. PYCARD-AS1 is such a discrete lncRNA, which exhibits a dual nuclear and cytoplasmic localization. Here, we provide a comprehensive picture of how PYCARD-AS1 works at different cellular compartments to regulate the pro-apoptotic gene PYCARD at both the epigenetic and translational levels, thereby contributing to the apoptotic regulation. Our study adds a different layer to the lncRNA-mediated regulation of gene expression, and strongly suggests that the transcripts of a specific lncRNA may have distinct functionalities at different cellular compartments where they are located.