Research Papers:
Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1
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Abstract
William Hankey1, Zhong Chen2, Maxwell J. Bergman1, Max O. Fernandez1, Baris Hancioglu3, Xun Lan4, Anil G. Jegga5, Jie Zhang6, Victor X. Jin7, Bruce J. Aronow5, Qianben Wang2 and Joanna Groden1
1Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America
2Department of Pathology, Duke University School of Medicine, Durham, North Carolina, United States of America
3Biomedical Informatics Shared Resource, The Ohio State University, Columbus, Ohio, United States of America
4Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China
5Division of Bioinformatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
6Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
7Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
Correspondence to:
Joanna Groden, email: [email protected]
Keywords: APC; AP-1; canonical WNT signaling; chromatin; colorectal cancer
Received: February 06, 2018 Accepted: July 05, 2018 Published: July 27, 2018
ABSTRACT
Mutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling.
289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.
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