Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number247
JournalGenome biology
Volume21
Issue number1
DOIs
StatePublished - Sep 15 2020

Keywords

  • 3D genome organization
  • CTCF
  • Enhancer
  • Gene regulation
  • Integrative analysis
  • NOTCH1
  • T cell lymphoblastic leukemia
  • Transcription factor

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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