CTCF expression and dynamic motif accessibility modulates epithelial�mesenchymal gene expression

Johnson, KS and Hussein, S and Chakraborty, P and Muruganantham, A and Mikhail, S and Gonzalez, G and Song, S and Jolly, MK and Toneff, MJ and Benton, ML and Lin, YC and Taube, JH (2022) CTCF expression and dynamic motif accessibility modulates epithelial�mesenchymal gene expression. In: Cancers, 14 (1).

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Abstract

Epithelial�mesenchymal transition (EMT) and its reversal, mesenchymal�epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET, or partial states promotes migration, invasion, dormancy, and metastatic colo-nization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular pheno-types during stepwise reversible EMT. We find that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET, and is lower in triple-negative breast cancer cell lines with EMT features. Through an analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs, but also by a diminished enrichment for CTCF binding motifs. Through a loss-of-function analysis, we demonstrate that the suppression of CTCF alters cellular plasticity, strengthening the epithelial phenotype via the upregulation of epithelial markers E-cadherin/CDH1 and downregulation of N-cadherin/CDH2. Conversely, the upregulation of CTCF leads to the upregulation of EMT gene expression and an increase in mesenchymal traits. These findings are indicative of a role of CTCF in regulating epithelial�mesenchymal plasticity and gene expression. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Item Type:	Journal Article
Publication:	Cancers
Publisher:	MDPI
Additional Information:	The copyright for this article belongs to MDPI
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	20 Jan 2022 06:52
Last Modified:	20 Jan 2022 06:52
URI:	http://eprints.iisc.ac.in/id/eprint/70988

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