The canonical WNT signaling pathway is necessary for guiding cell growth during embryonic development. In adults, WNT signaling maintains tissue stem cells and therefore plays an essential role in tissue homeostasis. In the colon, the WNT transcription factor, TCF4, is necessary for maintaining the intestinal stem cells. The initiating event in colon cancer is the aberrant activation of the WNT signaling pathway, which results in constitutive activity of TCF4. To determine how TCF4 influences colon cancer cell behavior, we silenced TCF7L2, the gene encoding TCF4, and used RNA sequencing and Hi-C to measure changes in transcription and nuclear structure in the SW480 colon cancer cell line. Loss of TCF4 resulted in A/B compartment switching, local chromatin reorganization, and a dramatic up-regulation in transcription. However, A/B compartment switching was not associated with changes in gene expression. We also found that loss of TCF4 resulted in the up-regulation of LEF1, another WNT transcription factor. Expressed LEF1 isoforms were found to be transcriptionally competent and over-compensated for WNT signaling activity upon loss of TCF4, suggesting a WNT-intrinsic feedback mechanism. Over-expression of LEF1 altered WNT signaling output to favor the expression of lymphoid genes, as opposed to a TCF4-based transcriptional program. ChIP-seq demonstrated that TCF4 and LEF1 bind distinct target genes, though they synergize to express MYC. TCF4 was found to bind the LEF1 promoter, indicative of direct repression, though LEF1 did not bind the TCF7L2 promoter. The CtBP1 protein, a known binding partner of TCF4, was found to be the most potent repressor of LEF1 expression. This demonstrates that despite the overall activation of WNT signaling in colon cancer, repressive functions of the WNT transcription factors are still intact, and the repression of LEF1 by TCF4 maintains a TCF4-centric transcriptional program in colon cancer cells.