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

Next, we found that genes with at least one nearby FLCspecific enhancer containing either a FOSL2/JUN or CREB motif are over-represented in the MAPK signaling pathway (KEGG 2016, p=0 .032, Fisher's exact test) and significantly enriched for MAPK1 (ERK2) targets and interacting proteins (PPI Hub Proteins, p=5.4 ´ 10 -6 , Fisher's exact test). We then ranked genes according to the density of FLC-specific enhancers containing both FOSL2/JUN and CREB motifs Tables showing results of transcription factor motif enrichment in FLC-specific TREs compared to non-FLC-specific TREs (D), FLC-specific promoters compared to non-FLCspecific promoters (F), and FLC-specific enhancers compared to non-FLCspecific enhancers (G). Full results are shown in Table S3 . (E) GREAT analysis of predicted promoter motifs in genes associated with FLC-specific TREs. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.01.18.911297 doi: bioRxiv preprint (Fig. 3F) , and observed that genes with at least one nearby FLC-specific enhancer containing both FOSL2/JUN and CREB motifs are enriched for MAPK1 and MAPK3 (ERK1) targets and interacting proteins (Fig. 3G ). Taken together, these results suggest that the regulation of genes such as CA12, SLC16A14, and LINC00473 by FLC-specific enhancers may be mediated through FOSL2/JUN and CREB and that these transcription factors may contribute to and/or result from dysregulated MAPK signaling.