Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

Celestia Fang,Kathryn A Helmin,Zhenjia Wang,Valentina Serafin,Aakrosh Ratan,Benjamin D Singer,Maria E Figueroa,Giuseppe Basso,Cuijuan Han,Stephanie L Safgren,Panagiotis Ntziachristos,Emmalee R Adelman,Alexandre Gaspar-Maia,Kyle P Eagen,Chongzhi Zang

doi:10.1186/s13059-020-02152-7

Abstract

BackgroundThe 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.ResultsTo 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.ConclusionsSpecific 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.

Highlights

The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer
We validated our findings in T cell acute lymphoblastic leukemia (T-ALL) and found that gained CCCTC-binding factor (CTCF) binding sites are potentially incurred by the activity of oncogenic transcription factor (TF) such as NOTCH1. These findings show that cancers exhibit an oncogenic CTCF binding signature that is intimately tied to chromatin topology and dysregulated
We identified 22,097 constitutive CTCF binding sites, which were defined as binding present in at least 80% of all 771 datasets determined by an empirical model (Fig. 1b, Additional file 1: Fig. S1d)

Summary

Introduction

The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. Studies have shown that various protein factors have roles in chromatin folding that is required for proper gene expression [3, 6,7,8,9]. One such factor is CCCT C-binding factor (CTCF), a DNA-binding protein that induces chromatin looping and binds at TAD boundaries [10]. Our previous studies using T cell acute lymphoblastic leukemia (TALL) models have shown that cell-type conserved constitutive CTCF binding sites frequently occur at chromatin domain boundaries and facilitate interactions between TFbound distal enhancers and their target genes [13]. While CTCF binding at TAD boundaries is usually conserved across diverse cell types and throughout development [15], we and others have shown that CTCF binding within TADs can exhibit tissue specificity [14, 16,17,18]

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