Abstract A27: Epigenomic and transcriptional analyses in a Tet-Myc driven mouse model of liver cancer

Abstract

Abstract The c-myc proto-oncogene is frequently overexpressed in human hepatoblastoma due to gene amplification or constitutively active Wnt signaling. High Myc levels characterize an aggressive hepatoblastoma subtype, reproduced in mice with a liver-specific tetracyclin-regulated c-myc transgene (1, 2). Here, we used an analogous mouse model (tetO-MYC/Lap-tTA; ref. 3) to study the epigenomic and transcriptional mechanisms underlying tumor progression and maintenance. Tet-Myc induction in utero resulted in rapid and fully penetrant tumorigenesis by the age of six weeks. Pre-tumoral changes were detectable already at a late embryonic stage (E18.5) with increased liver size and hepatoblast fraction. As previously described (2), tumors remained dependent on the constitutive expression of the transgene. To study transcriptional changes during tumor progression and regression, we established RNA-seq profiles in control hepatoblasts, pre-tumoral Tet-Myc hepatoblasts and tumor nodules, in the latter before and after short-term inactivation of Tet-Myc. In parallel, we used ChIP-seq to profile the genome-wide distribution of Myc, RNAPII and several histone marks (H3K4me1, H3K4me3, H3K27ac), yielding comprehensive maps of Myc binding to regulatory elements (promoters and enhancers). This unique dataset is providing the basis for mechanistic studies addressing how Myc deregulates its target genes during liver tumorigenesis: comparison of differentially expressed mRNAs and Myc-binding profiles enables us to discriminate between directly and potentially indirectly regulated genes, for which we are currently investigating the underlying molecular basis. Furthermore, our genome-wide data are allowing us to unravel potentially druggable genes and pathways regulated by Myc during hepatoblastoma progression and maintenance. Our progress in characterizing this model will be presented at the meeting.