Gene coding regions only represent less than 2% of the human genome. The non-coding genome also plays a pivotal role in many aspects of the normal cellular activities, as they could regulate the transcription of genes. Aberrant amplification and mutations in these regions can cause diseases such as cancer. The functions of non-coding regulatory elements have not been thoroughly studied. We have developed a novel high-throughput system to study the silencer regions of the genome. In addition, we have also developed a unique screening system using CRISPR/Cas9 to study the function of the non-coding regulatory genome. Main research strategies consist of designing custom screen libraries, performing genome-wide CRISPR functional screening, applying ATAC-seq, ChIP-seq, RNA-seq, CRISPR/Cas9 genome editing, cell imaging, human stem cell differentiation assays, and bioinformatics analyses. The ultimate goal is to identify important non-coding regions that can be used for personalized diagnosis of diseases and rationale treatment design.