Using a novel temporal RNA-Seq and ChIP-Seq experimental design, we demonstrate that TCF7L2 regulates over 400 genes in hepatoma cells, and that early gene expression changes (≤18 h post-Tcf7l2 silencing) and a strong proximal presence of TCF7L2 (peak proximity score > 10), indicate that TCF7L2 directly regulates 149 of these genes in hepatoma cells. Here, TCF7L2 is linked to hepatocellular carcinoma.