Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma

Rochelle L. Tiedemann, Ryan A. Hlady, Paul D. Hanavan, Douglas Lake, Raoul Tibes, Jeong Heon Lee, Jeong Hyeon Choi, Thai H. Ho, Keith D. Robertson

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1927-1946
Number of pages20
Issue number2
StatePublished - 2016


  • DNA methylation
  • Epigenetics
  • Histone methylation
  • Renal cell cancer
  • SETD2

ASJC Scopus subject areas

  • Oncology


Dive into the research topics of 'Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma'. Together they form a unique fingerprint.

Cite this