This study demonstrates that dCas9-VP64 fusion proteins can be used to activate endogenous human genes through RNA-guided targeting. dCas9, a catalytically inactive form of the CRISPR-associated nuclease, can be fused with the VP64 transcriptional activation domain to create a protein that can be directed by single or multiple guide RNAs (gRNAs) to increase expression of specific endogenous genes. The researchers tested this approach by targeting the VEGFA and NTF3 genes in human cells, showing that dCas9-VP64 could significantly increase the expression of these genes when targeted by specific gRNAs. They also found that combining multiple gRNAs could lead to synergistic activation of gene expression, suggesting that this method could be used for combinatorial control of gene expression. The study also highlights the potential of this approach for future applications in biological research and synthetic biology. However, the magnitude of gene expression increases observed with dCas9-VP64 was generally lower than that seen with TALE-based activators. The researchers also note the need for further studies to determine the off-target effects of RNA-guided activators, as these can be difficult to predict. Overall, the study provides proof-of-principle that heterologous effector domains can be fused to dCas9 without disrupting its ability to function with sgRNAs in mammalian cells. This opens the door to the fusion of dCas9 with other novel effector domains, such as histone modifying enzymes and DNA methylation modifiers.This study demonstrates that dCas9-VP64 fusion proteins can be used to activate endogenous human genes through RNA-guided targeting. dCas9, a catalytically inactive form of the CRISPR-associated nuclease, can be fused with the VP64 transcriptional activation domain to create a protein that can be directed by single or multiple guide RNAs (gRNAs) to increase expression of specific endogenous genes. The researchers tested this approach by targeting the VEGFA and NTF3 genes in human cells, showing that dCas9-VP64 could significantly increase the expression of these genes when targeted by specific gRNAs. They also found that combining multiple gRNAs could lead to synergistic activation of gene expression, suggesting that this method could be used for combinatorial control of gene expression. The study also highlights the potential of this approach for future applications in biological research and synthetic biology. However, the magnitude of gene expression increases observed with dCas9-VP64 was generally lower than that seen with TALE-based activators. The researchers also note the need for further studies to determine the off-target effects of RNA-guided activators, as these can be difficult to predict. Overall, the study provides proof-of-principle that heterologous effector domains can be fused to dCas9 without disrupting its ability to function with sgRNAs in mammalian cells. This opens the door to the fusion of dCas9 with other novel effector domains, such as histone modifying enzymes and DNA methylation modifiers.