Fosl1 is a transcriptional effector of BRAFV600E-driven intestinal tumorigenesis

The serrated neoplasia pathway in an alternate route to colorectal cancer (CRC) development where BRAFV600E is the most common initiating genetic alteration. BRAFV600E-driven tumorigenesisrequires gene expression changes mediated by activation of the ERK MAPK signalling pathway. However, the key effectors of this process are elusive. Here, we identify the ERK-regulated transcription factor Fosl1 one such effector. We show that Fosl1 is dispensable for the initiation ofBRAFV600E-driven serrated neoplasia in mice but promotes progression of the disease by regulatingthe expression of genes involved in inflammation, immunity, cell cycle control, fetal-likeprogramming, and gastric metaplasia. Notably, transgenic Fosl1 expression alone was sufficient to induce tumours with a BRAFV600E-like serrated morphology and transcriptional profile. Thesefindings reveal a mechanism through which oncogenic BRAF-driven ERK signalling reprograms transcription to drive serrated neoplasia. Overall design: RNA-seq using Illumina paired-ends of polyA transcriptomes comparing mouse normal intestinal epithelium to BRAF mutant and FLAG-Fosl1 transgene tumours and to BRAF mutant with or without Fosl1