Identification of TNF-α-Responsive Promoters and Enhancers in the Intestinal Epithelial Cell Model Caco-2

The Caco-2 cell line is one of the most important in vitro models for enterocytes, and is used to study drug absorption and disease, includingi nflammatory bowel disease and cancer. In order to use the model optimally, it is necessary to map its functional entities. In this study, we have generated genome-wide maps of active transcription start sites (TSSs), and active enhancers in Caco-2 cells with or without tumour necrosis factor (TNF)-alpha stimulation to mimic an inflammatory state. We found 520 promoters that significantly changed their usage level upon TNF-alpha stimulation; of these, 52% are not annotated. A subset of these has the potential to confer change in protein function due to protein domain exclusion. Moreover, we locate 890 transcribed enhancer candidates, where similar to 50% are changing in usage after TNF-alpha stimulation. These enhancers share motif enrichments with similarly responding gene promoters. As a case example, we characterize an enhancer regulating the laminin-5 gamma 2-chain (LAMC2) gene by nuclear factor (NF)-kappa B binding. This report is the first to present comprehensive TSS and enhancer maps over Caco-2 cells, and highlights many novel inflammation specific promoters and enhancers.