Fig. 1

a Cas knockout is accomplished by targeted indel formation at a genomic site complementary to the sgRNA. An indel often results in a frameshift that causes premature stop codon formation that leads to non-sense-mediated decay (NMD) of target mRNAs or the generation of truncated non-functional proteins. b Programmable transcription repression can be achieved using dCas and repressor domains (e.g., KRAB) that are fused to the dCas. This complex either directly sterically hinders the recruitment of native transcription factors and RNA polymerase, or rewrites the nearby chromatin region to be more silencing to affect transcription status, leading to the reduced production of target mRNA and functional protein. c Programmable transcription activation can be achieved using dCas and activator domains (e.g., VP64, p65, and Rta) that are fused to the dCas. This complex recruits transcriptional machinery to the transcription start site of the desired gene, resulting in enhanced expression of the target mRNA and functional protein. NHEJ, non-homologous end joining; TF, transcription factor; Pol II, RNA polymerase II; PAM, protospacer adjacent motif