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Chromosomal position effect, also known as position effect variegation, has been extensively studied for almost a century. A systematic approach to study positional effect is to isolate genetic from epigenetic factors specifically to measure the expression of the same gene positioned in different chromatin contexts. Current strategies to target a reporter gene at multiple genomic locations are not capable of increasing both the sensitivity and throughput of data. Here, we developed a new massively parallel method to create and identify isogenic reporter clones. This method allowed us to interrogate the effect of chromatin environment on gene expression variability and epigenetic drug sensitivity as well as identify their underlying mechanisms. In human cells, we found that the protein expression mean and noise significantly are varied by the genomic location of the gene. By mapping our measurements of reporter expression at different genomic loci with epigenetic profiles of the transcription factor enrichment and the distance to chromatin states, we identified the factors that impact gene regulation. Some factors are involved in mediating both gene expression mean and noise, while other only control one of these features. Moreover, we discovered wide-spread loci-specific sensitivities to epigenetic drugs for three distinct chemical compounds that target histone deacetylase, DNA methylation and bromodomain proteins. By leveraging ENCODE data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by these epigenetic drugs.