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 further investigate the uniqueness of the 10 FLC-specific enhancer hotspots not present in SEdb, we cross-referenced these enhancer hotspots to individual enhancers identified by the ENCODE, FANTOM5, and NIH Roadmap Epigenomics consortia (see Materials and Methods). Only one FLC-specific enhancer hotspot (located near MRC1) did not overlap any individual enhancers recorded in the three databases mentioned above, suggesting this enhancer hotspot is truly unique to FLC (Fig. 5H ). We also recalculated the signal for the same 10 FLC-specific super enhancers including only those individual enhancers that do not overlap with any enhancers from the three databases. Only the revised stitched enhancers close to MRC1 and SLC16A14 exhibited enough transcriptional activity (ChRO-seq signal) to still meet the threshold set in our original analysis for an enhancer hotspot. These results suggest that there is a substantial amount of enhancer activity that is potentially completely unique to FLC at the MRC1 and SLC16A14 loci.