The epigenome is comprised of chemical modifications to DNA and histone proteins that regulate chromatin structure and DNA accessibility. Given the variety and complexity of epigenetic modifications, and the diverse repertoire of enzymes that regulate them, understanding the role of these modifications in transcriptional regulation will require comprehensive exploration of their combinatorial activities. While first generation epigenome engineering tools using single catalytic domains allow targeted editing of DNA and histone modifications, they frequently underperform in efficacy and stability. Consequently, we will deeply probe the combinatorial effects of recruiting multiple epigenome modifying enzymes simultaneously to target loci in the human genome, investigating their causal roles in genome regulation. This will provide new insights into how epigenome modification pathways function to regulate gene expression, while developing a range of novel epigenome editing systems for synthetic biology applications.