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

Super enhancers are non-coding regions exhibiting unusually high transcriptional activity Lovén et al., 2013; Pott and Lieb, 2015; Whyte et al., 2013) and are important regulators of cell identity Whyte et al., 2013) and key cancer genes Lovén et al., 2013) . We used an algorithm analogous to ones previously used to define super enhancers from chromatin immunoprecipitation and sequencing (ChIP-seq) data (Lovén et al., 2013; Whyte et al., 2013) to identify clusters of enhancers that have remarkably high transcriptional activity in FLC, but not in NML (Fig. 5A , see Materials and Methods). Using FLC-specific enhancers as input, we identified 141 dense clusters with especially high FLC-specific transcriptional activity (Fig. 5B ). Because these loci consist of only FLCspecific enhancers instead of all enhancers present in FLC, we refer to them as "FLC-specific enhancer hotspots" rather than FLC super enhancers.