Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation

Genome Biology

Zhenjia Wang¹  Aakrosh Ratan²  Chongzhi Zang²  Cuijuan Han³  Kyle P. Eagen³  Celestia Fang³  Benjamin D. Singer⁴  Panagiotis Ntziachristos⁵  Kathryn A. Helmin⁶  Stephanie L. Safgren⁷  Alexandre Gaspar-Maia⁷  Valentina Serafin⁸  Giuseppe Basso⁹  Emmalee R. Adelman^1,10  Maria E. Figueroa^1,10 

[1] Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA;Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA;Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA;UVA Cancer Center, University of Virginia, Charlottesville, VA, USA;Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA;Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA;Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;Department of Medicine, Division of Pulmonary and Critical Care, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA;Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA;Department of Medicine, Division of Pulmonary and Critical Care, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA;Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;Oncohematology Laboratory, Department of Women’s and Children’s Health, University of Padova, Padova, Italy;Oncohematology Laboratory, Department of Women’s and Children’s Health, University of Padova, Padova, Italy;Italian Institute for Genomic Medicine, 10060, Torino, Italy;Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA;Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA;

关键词: CTCF;    3D genome organization;    Integrative analysis;    Gene regulation;    Transcription factor;    Enhancer;    T cell lymphoblastic leukemia;    NOTCH1;   

DOI  :  10.1186/s13059-020-02152-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY