Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are enriched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs.
Cell. 2023 Jun 09 [Epub ahead of print]
Hongshan Guo, Joanna A Vuille, Ben S Wittner, Emily M Lachtara, Yu Hou, Maoxuan Lin, Ting Zhao, Ayush T Raman, Hunter C Russell, Brittany A Reeves, Haley M Pleskow, Chin-Lee Wu, Andreas Gnirke, Alexander Meissner, Jason A Efstathiou, Richard J Lee, Mehmet Toner, Martin J Aryee, Michael S Lawrence, David T Miyamoto, Shyamala Maheswaran, Daniel A Haber
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA., Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA., Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Engineering in Medicine and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114, USA., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: ., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: ., Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: .