CRISPRi screens identify the lncRNA, LOUP , as a multifunctional locus regulating macrophage differentiation and inflammatory signaling

• DOI: 10.1073/pnas.2322524121
• Publication Date: 2024-05-23T17:40:09Z
• Authors: Haley Halasz; Eric Malekos; Sergio Covarrubias; Samira Yitiz; Christy Montano; Lisa Sudek; Sol Katzman; S. John Liu; Max A. Horlbeck; Leila Namvar; Jonathan S. Weissman; Susan Carpenter
• Keywords: Monocyte

Long noncoding RNAs (lncRNAs) account for the largest portion of RNA from transcriptome, yet most their functions remain unknown. Here, we performed two independent high-throughput CRISPRi screens to understand role lncRNAs in monocyte function and differentiation. The first was a reporter-based screen identify that regulate TLR4-NFkB signaling human monocytes second identified involved macrophage We successfully numerous protein-coding genes can positively or negatively inflammation To functional roles both processes, chose further study lncRNA LOUP [lncRNA originating upstream regulatory element SPI1 (also known as PU.1)], it emerged top hit screens. Not only does its neighboring gene, myeloid fate–determining factor , thereby affecting differentiation, but knockdown leads broad upregulation NFkB-targeted at baseline upon activation. also harbors three small open reading frames capable being translated are responsible ’s ability TLR4/NFkB signaling. This work emphasizes value screening rapidly innate immune system.