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

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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1927-1946
Number of pages20
JournalOncotarget
Volume7
Issue number2
DOIs
StatePublished - 2016

Fingerprint

DNA Methylation
Renal Cell Carcinoma
Developmental Genes
Phenotype
Cell Line
Neoplasms
Mutation
Intergenic DNA
DNA
Transcriptome
Epigenomics
Chromatin
Carcinogenesis
Genotype
Genome
Genes
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. / Tiedemann, Rochelle L.; Hlady, Ryan A.; Hanavan, Paul D.; Lake, Douglas F.; Tibes, Raoul; Lee, Jeong Heon; Choi, Jeong Hyeon; Ho, Thai H; Robertson, Keith D.

In: Oncotarget, Vol. 7, No. 2, 2016, p. 1927-1946.

Research output: Contribution to journalArticle

Tiedemann, RL, Hlady, RA, Hanavan, PD, Lake, DF, Tibes, R, Lee, JH, Choi, JH, Ho, TH & Robertson, KD 2016, 'Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma', Oncotarget, vol. 7, no. 2, pp. 1927-1946. https://doi.org/10.18632/oncotarget.6481
Tiedemann, Rochelle L. ; Hlady, Ryan A. ; Hanavan, Paul D. ; Lake, Douglas F. ; Tibes, Raoul ; Lee, Jeong Heon ; Choi, Jeong Hyeon ; Ho, Thai H ; Robertson, Keith D. / Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 2. pp. 1927-1946.
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