Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

Timothy A. Dinh; Ramja Sritharan; F. Donelson Smith; Adam B. Francisco; Rosanna K. Ma; Rodica P. Bunaciu; Matt Kanke; Charles G. Danko; Andrew P. Massa; John D. Scott; Praveen Sethupathy

To identify putative targets of FLC-specific enhancers, we employed computational approaches based on enhancer density and signal correlation. We identified 141 FLC-specific enhancer hotspots, defined as dense clusters of enhancers with especially high transcriptional activity (similar to the concept of super enhancers). Comparing these loci with previously characterized super enhancers in SEdb, we found that 10 FLC-specific enhancer hotspots are completely unique and do not overlap with any known super enhancer. Furthermore, 72 of the enhancer hotspots do not overlap with super enhancers from any previously assayed liver tissue or liver-derived cells. As super enhancers have been shown to regulate cell identity and oncogenes Lovén et al., 2013) , our findings suggest that these FLC-specific enhancer hotspots may regulate genes important in the formation, progression, and/or maintenance of this cancer. Super enhancers are regulated by the bromodomain protein BRD4 (Lovén et al., 2013) , and BRD4 inhibitors such as JQ1 (Filippakopoulos et al., 2010) have been shown to disrupt super enhancer function (Gryder et al., 2017; Lovén et al., 2013; Mack et al., 2018; Peeters et al., 2015) . Pharmacological disruption of the FLC-specific enhancer hotspots we have described here may represent an alternative therapeutic approach for FLC.