TCF7L2 silencing results in altered gene expression patterns accompanied by local genomic reorganization.
Canonical Wnt signaling is crucial for intestinal homeostasis as TCF4, the major Wnt signaling effector in the intestines, is required for stem cell maintenance. The capability of TCF4 to maintain the stem cell phenotype is contingent upon β-catenin, a potent transcriptional activator, which interacts with histone acetyltransferases and chromatin remodeling complexes. We used RNAi to explore the influence of TCF4 on chromatin structure (Hi-C) and gene expression (RNA sequencing) across a 72-hour time series in colon cancer. We found that TCF4 reduction results in a disproportionate up-regulation of gene expression, including a powerful induction of SOX2. Integration of RNA sequencing and Hi-C data revealed a TAD boundary loss, which occurred concomitantly with the over-expression of a cluster of CEACAM genes on chromosome 19. We identified EMT and E2F as the 2 most deregulated pathways upon TCF4 depletion and LUM, TMPO, and AURKA as highly influential genes in these networks using measures of centrality. Results from gene expression, chromatin structure, and centrality analyses were integrated to generate a list of candidate transcription factors crucial for colon cancer cell homeostasis. The top ranked factor was c-JUN, an oncoprotein known to interact with TCF4 and β-catenin, confirming the usefulness of this approach.
['Brown|Markus A|MA|', 'Dotson|Gabrielle A|GA|', 'Ronquist|Scott|S|', 'Emons|Georg|G|', 'Rajapakse|Indika|I|', 'Ried|Thomas|T|']
D020413:3' Untranslated Regions D045744:Cell Line, Tumor D002843:Chromatin D000081204:Chromatin Immunoprecipitation Sequencing D003110:Colonic Neoplasms D019295:Computational Biology D020869:Gene Expression Profiling D005786:Gene Expression Regulation D020868:Gene Silencing D006801:Humans D005810:Multigene Family D034622:RNA Interference D034741:RNA, Small Interfering D058118:Transcription Factor 7-Like 2 Protein D014157:Transcription Factors D060449:Wnt Signaling Pathway
TCF7L2 Wnt Signaling TCF4 Chromatin structure Colon Cancer