LincRNA-p21 Activates p21 In cis to Promote Polycomb Target Gene Expression and to Enforce the G1/S Checkpoint

The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression. [Display omitted] •Murine knockout model reveals a role for lincRNA-p21 in activating p21 in cis•LincRNA-p21 acts with hnRNP-K as a transcriptional coactivator of p53•LincRNA-p21 promotes the expression of a set of Polycomb target genes via p21•LincRNA-p21 regulates the G1/S checkpoint, proliferation, and reprogramming Using a genetic approach, Dimitrova et al. show that the p53-regulated lncRNA, lincRNA-p21, promotes in cis the expression of its neighbor, p21. Loss of lincRNA-p21 phenocopies p21 deficiency, leading to defective G1/S checkpoint function, increased proliferation rates, enhanced reprogramming efficiency, and deregulated expression of a set of Polycomb target genes.