Loss of function of /, also known as / [encoding p16, p15, and p14 (mouse p19)], confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand the transcriptional regulation of , a CRISPR screen targeting open, noncoding chromatin regions adjacent to was performed in a human reporter cell line. We identified a repressive element located in the 3' region adjacent to the promoter that controls expression via long-distance chromatin interactions. Coinfection of lentiviral dCas9-KRAB with selected single-guide RNAs against the repressive element abrogated the / chromatin contacts, thus reactivating expression. Genetic CRISPR screening identified candidate transcription factors inhibiting regulation, including ZNF217, which was confirmed to bind the / interaction loop. In summary, direct physical interactions between and genes provide mechanistic insights into their cross-regulation.