SRP343264 PRJNA774807 GSE186618 Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer [RNA-seq] Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the processes that configure these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are an abundant source of enhancers that mediate transcriptional dysregulation in cancer. In colorectal cancer and other epithelial tumors, AP1 signaling drives aberrant activation of enhancers derived from the primate-specific ERV family LTR10. CRISPR studies revealed that LTR10 elements control colorectal cancer-specific gene expression at multiple loci associated with tumorigenesis. Within the human population, individual LTR10 elements show extensive structural variation due to repeat instability of an internal variable number tandem repeat (VNTR) region that affects AP1 binding. Our findings reveal that ERV-derived enhancers link oncogenic signaling to transcriptional dysregulation and shape the evolution of cancer-specific regulatory networks. Overall design: Transcriptional profiling (RNA-seq) of a colorectal cancer cell line (HCT116) that was either untreated or treated with 100 ng/mL Cobimetinib or TNF-alpha for 24 hr. RNA-seq is also provided from clonal HCT116 lines that stably express Cas9 and pairs of gRNAs targeting LTR10 elements near genes: ATG12, XRCC4, MEF2D, FGF2, MCPH1. As well as silencing of the TSS of the following genes: FOSL1 and cJUN and ATG12; and CRISPR knockout of an LTR10 element within gene KDM6A. Finally, RNA-seq is also provided for HCT116 cell line-based xenografts (CDXs) that were either treated with trametinib or a vehicle control. CDX samples were established from HCT116 cells that were engrafted into two immunodeficient mice. Trametinib was purchased from Selleck Chemicals and dissolved in 10% Cremophor EL+5% PEG400 in water. The drug was dosed at 0.125 mg/kg by oral gavage daily for 21 days. Replicates are derived from the left and right flanks of mouse 0 (trametinib-treated) and mouse 95 (treated with a vehicle). GSE186618 pubmed 39018396 parent_bioproject PRJNA774805