Abstract 5181: Global alteration of CTCF binding in the cancer genome

Abstract

Abstract The goal of this study is to understand the functions of altered CTCF binding in the cancer genome and its role in tumorigenesis. CTCF is a zinc finger protein that binds to DNA and functions as a transcriptional factor (TF) or a chromatin insulator. Disruption of individual CTCF bindings have been reported in several systems that associate with DNA methylation changes and result in aberrant chromatin interaction and differential expression of genes associated with the topological associated domains (TADs). We systematically analyzed over 500 CTCF ChIP-seq datasets across different human tissues and identified cancer-specific aberrant (gained) and disrupted (lost) CTCF binding sites in several cancer types. Through integrative analysis with other genomic data including RNA-seq, hi-C and DNA methylation profiles, we found that CTCF binding alterations correlate with differential chromatin interaction in the TADs, but most altered binding sites do not have DNA methylation changes. Instead, lost CTCF bindings at gene promoter regions associate with transcriptional repression, while gained bindings primarily occur in the distal enhancer regions bound by oncogenic transcription factors inducing gene expression. We validated these findings in T-cell acute lymphoblastic leukemia (T-ALL) using patient derived samples and identified NOTCH1 among oncogenic TFs bound at enhancers co-occupied with T-ALL-specific gained CTCF binding. These findings indicate that alteration of CTCF binding is an epigenomic signature of cancer cells, and our approach demonstrates a framework of integrating existing multi-omics data for mechanistic studies of cancer gene regulation. Citation Format: Celestia Fang, Zhenjia Wang, Carlos A. Martinez, Panagiotis Ntziachristos, Chongzhi Zang. Global alteration of CTCF binding in the cancer genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5181.