Dataset Information

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

ABSTRACT: 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 ?-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 ?-catenin, confirming the usefulness of this approach.

SUBMITTER: Brown MA

PROVIDER: S-EPMC7809436 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Brown Markus A MA Dotson Gabrielle A GA Ronquist Scott S Emons Georg G Rajapakse Indika I Ried Thomas T

Neoplasia (New York, N.Y.) 20210107 2

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 ...[more]

PMID: 33422939

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Project description:Primary human hepatocytes (PHHs) undergo dedifferentiation upon the two-dimensional (2D) culture, which particularly hinders their utility in long-term in vitro studies. Lipids, as a major class of biomolecules, play crucial roles in cellular energy storage, structure, and signaling. Here, for the first time, we mapped the alterations in the lipid profile of the dedifferentiating PHHs and studied the possible role of lipids in the loss of the phenotype of PHHs. Simultaneously, differentially expressed miRNAs associated with changes in the lipids and fatty acids (FAs) of the dedifferentiating PHHs were investigated. PHHs were cultured in monolayer and their phenotype was monitored morphologically, genetically, and biochemically for five days. The lipid and miRNA profile of the PHHs were analyzed by mass spectrometry and Agilent microarray, respectively. In addition, 24 key genes involved in the metabolism of lipids and FAs were investigated by qPCR. The typical morphology of PHHs was lost from day 3 onward. Additionally, ALB and CYP genes were downregulated in the cultured PHHs. Lipidomics revealed a clear increase in the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) containing lipids, but a decrease in the polyunsaturated fatty acids (PUFA) containing lipids during the dedifferentiation of PHHs. In line with this, FASN, SCD, ELOVL1, ELOVL3, and ELOVL7 were upregulated but ELOVL2 was downregulated in the dedifferentiated PHHs. Furthermore, differentially expressed miRNAs were identified, and the constantly upregulated miR-27a and miR-21, and downregulated miR-30 may have regulated the synthesis, accumulation and secretion of PHH lipids during the dedifferentiation. Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs' loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype.

Dataset Information

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

Publications

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

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