Next Generation Epigenomics for Oncology: Dissecting Noncoding Regulatory Elements in Cancer Genomes

Transcription Factors and the Epigenome
Transcription factors are key players in shaping the epigenome and determining cell fate/state in normal tissues and pathophysiological settings such as cancer. Techniques for epigenome mapping such as ChIP-seq are widely employed to characterize genome wide occupancy of TFs and the underlying features of the transcriptional regulatory elements they engage. However, such profiling techniques alone provide only a descriptive snapshot of a given cell’s cistrome.

A Multi-Omics Approach to Identify Novel Targets
The Galli laboratory employed high-throughput functional epigenomic screens to characterize which TF-bound regulatory elements are critical in driving specific phenotypes. Using Estrogen Receptor (ER) as a prototypical oncogenic transcription factor, they revealed that only a small subsets of ER-bound enhancers are necessary for ER-driven cancer cell proliferation. Such enhancers are enriched with specific ER co-factors GATA3 and TFAP2C.

By combining CRISPR screens coupled to single cells RNA-seq (CROP-seq) and 3D Hi-C maps, they reconstructed the minimal transcriptional network engaged by Estrogen Receptor to propagate its oncogenic proliferative program and identified TFAP2C as a novel target in ER-positive luminal breast cancer.