title: Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma.
abstract: Clear cell renal cell carcinomas (ccRCCs) harbor frequent mutations in epigenetic modifiers including SETD2, the H3K36me3 writer. We profiled DNA methylation (5mC) across the genome in cell line-based models of SETD2 inactivation and SETD2 mutant primary tumors because 5mC has been linked to H3K36me3 and is therapeutically targetable. SETD2 depleted cell line models (long-term and acute) exhibited a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 centered across intergenic regions adjacent to low expressing genes, which became upregulated upon dysregulation of the epigenome. Poised enhancers of developmental genes were prominent hypermethylation targets. SETD2 mutant primary ccRCCs, papillary renal cell carcinomas, and lung adenocarcinomas all demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype and advanced grade. These findings collectively demonstrate that SETD2 mutations drive tumorigenesis by coordinated disruption of the epigenome and transcriptome,and they have important implications for future therapeutic strategies targeting chromatin regulator mutant tumors.
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Tiedemann
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Hlady
authors.affiliation: School of Life Sciences, Mayo Clinic Collaborative Research Building, Arizona State University, Scottsdale, AZ, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Hanavan
authors.affiliation: School of Life Sciences, Mayo Clinic Collaborative Research Building, Arizona State University, Scottsdale, AZ, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Lake
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.|Epigenomics Translational Program, Center for Individualized Medicine, Rochester, MN, USA.
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.affiliation: Epigenomics Translational Program, Center for Individualized Medicine, Rochester, MN, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, Georgia Regents University, Augusta, GA, USA.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.|Epigenomics Translational Program, Center for Individualized Medicine, Rochester, MN, USA.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.|Epigenomics Translational Program, Center for Individualized Medicine, Rochester, MN, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Robertson
mesh_terms: D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; D012333:RNA, Messenger; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human
keywords: DNA methylation; SETD2; epigenetics; histone methylation; renal cell cancer