Targeted activation of endogenous genes is an important approach for cell engineering. Here, we report that the nuclease-deactivated dCas9 fused to a transcriptional activator (VPR) and an epigenetic effector (the catalytic domain of histone acetyltransferase p300core) simultaneously, sequentially, or as a single quadripartite effector can lead to enhanced activation of target genes. The composite activator, VPRP, behaves more efficiently than individual activators across a set of genes in different cell types. We characterize off-target effects for host chromatin acetylation and transcriptome using the effectors. Our work demonstrates that transcriptional and epigenetic effectors can be used together to enhance gene activation and suggests the need for further optimization of epigenetic effectors to reduce off-targets.