Human primary monocytes are critical in controlling immune responses and tissue homeostasis. However, to identify and study molecular components that underlie the function of these cells, there remains a need to develop methods to perturb genes in these cells. Here we report lentiviral-based delivery of dCas9-KRAB and guide RNAs to efficiently silent target genes, such as CD45 and CD209. We further show that sgRNAs against TICAM1 dampen proinflammatory cytokine and interferon expression in

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... nse to lipopolysaccharide. When delivered by lentivirus, sgRNAs are incorporated into the genome, thus enabling pooled screening to perturb and identify coding and non-coding elements that contribute to the functions of primary human monocytes.