Epigenetics is the study of heritable traits driven by alterations in the genome that occur on top of the DNA sequences encoding our genome. These features include histone and DNA modifications, chromatin architecture, and transcription factors that enable the emergence of cell types and a diversity of traits that are responsive to external stimuli. The study of the epigenome has thus been important for understanding basic biology and human disease. Until the emergence of CRISPR/Cas systems for programmable gene/epigenome editing, the field of epigenetics relied heavily on observational studies and genome-wide correlations to reach conclusions on the role epigenetic features play. The rapid adoption of CRISPR-based tools allowed for the targeted modification of DNA and deposition of precise epigenetic modifications through the fusion of chromatin-modifying factors to a catalytically inactivated version of a CRISPR system. While promising in its use for both basic and translational applications, the field still requires improved tools and a better understanding of their function to address inherent toxicity and off-targeting concerns, especially with respect to histone acylation, a modification linked to gene activation. Using the widely adopted epigenome editing effector domain and histone acyltransferase, p300, I address these concerns by (1) engineering mutations into p300 to alter its acylation deposition profile and cytotoxicity and (2) applying multi-omics and functional genomics methods to characterize these effectors for off-targets and benchmark their utility in a non-coding enhancer mapping screen.