Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation
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RESEARCH
Open Access
Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation Celestia Fang1,2†, Zhenjia Wang3†, Cuijuan Han1,2, Stephanie L. Safgren4, Kathryn A. Helmin5, Emmalee R. Adelman6,7, Valentina Serafin8, Giuseppe Basso8,9, Kyle P. Eagen1,2, Alexandre Gaspar-Maia4, Maria E. Figueroa6,7, Benjamin D. Singer1,2,5, Aakrosh Ratan3,10,11, Panagiotis Ntziachristos1,2,12*† and Chongzhi Zang3,10,11*† * Correspondence: panos.ntz@ northwestern.edu; zang@virginia. edu † Celestia Fang and Zhenjia Wang contributed equally to this work. † Panagiotis Ntziachristos and Chongzhi Zang are co-senior authors of this work. 1 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA 3 Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA Full list of author information is available at the end of the article
Abstract Background: The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers. Results: To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena. Conclusions: Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer. Keywords: CTCF, 3D genome organization, Integrative analysis, Gene regulation, Transcription factor, Enhancer, T cell lymphoblastic leukemia, NOTCH1
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
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