TCF7L2 silencing results in altered gene expression patterns accompanied by local genomic reorganization

Neoplasia: An International Journal for Oncology Research

Thomas Ried¹  Georg Emons¹  Gabrielle A. Dotson²  Indika Rajapakse³  Scott Ronquist³  Markus A. Brown⁴ 

[1] Bioinformatics, University of Michigan, Ann Arbor, MI, USA;Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA;;Department of Computational Medicine &Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;

关键词: Colon Cancer;    Wnt Signaling;    Chromatin structure;    TCF4;    TCF7L2;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown