Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 36, Pages 9683-9688Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705236114
Keywords
nasopharyngeal carcinoma; super-enhancer; H3K27ac; Epstein-Barr virus; ETV6
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Funding
- National Institute of Allergy and Infectious Diseases [R01A1123420]
- National Cancer Institute [R01CA047006, R01CA170023, R01CA085180]
- International Cooperation Project of Science and Technology Plan of Guangdong Province [2014A050503033, 2016A050502011]
- Bristol-Myers Squibb Foundation for Immunology Research
- National Natural Science Foundation of China [81520108022]
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Nasopharyngeal carcinoma (NPC) most frequently occurs in southern China and southeast Asia. Epidemiology studies link NPC to genetic predisposition, Epstein-Barr virus (EBV) infection, and environmental factors. Genetic studies indicate that mutations in chromatin-modifying enzymes are the most frequent genetic alterations in NPC. Here, we used H3K27ac chromatin immune precipitation followed by deep sequencing (ChIP-seq) to define the NPC epigenome in primary NPC biopsies, NPC xenografts, and an NPC cell line, and compared them to immortalized normal nasopharyngeal or oral epithelial cells. We identified NPC-specific enhancers and found these enhancers were enriched with nuclear factor kappa B (NF-kappa B), IFN-responsive factor 1 (IRF1) and IRF2, and ETS family members ETS1 motifs. Normal cell-specific enhancers were enriched with basic leucine zipper family members and TP53 motifs. NPC super-enhancers with extraordinarily broad and high H3K27ac signals were also identified, and they were linked to genes important for oncogenesis including ETV6. ETV6 was also highly expressed in NPC biopsies by immunohistochemistry. High ETV6 expression correlated with a poor prognosis. Furthermore, we defined the EBV episome epigenetic landscapes in primary NPC tissue.
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