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

Precise spatial and temporal regulation of gene expression is essential to many biological processes. One class of cis-regulatory elements that plays a major role in transcriptional regulation of gene expression is enhancers. Enhancers are classically defined as stretches of non-coding DNA that promote transcription of target gene(s) irrespective of genomic context, orientation, and, to a substantial extent, distance as well (Blackwood and Kadonaga, 1998) . Enhancers are often cell-type specific, allowing precise spatiotemporal control of gene transcription in different cell types within an organism (Heintzman et al., 2009; Nord et al., 2013) . Recent work suggests that there are at least tens of thousands of active enhancers in any given cell type (Dunham et al., 2012) . Active enhancers serve as binding sites for transcription factors, transcriptional coactivators, and RNA polymerase and are thought to interact with their cognate promoters through three-dimensional looping, explaining their ability to act over long distances (Long et al., 2016) .