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 language | English (US) |
|---|---|
| Pages (from-to) | 1927-1946 |
| Number of pages | 20 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma
AU - Tiedemann, Rochelle L.
AU - Hlady, Ryan A.
AU - Hanavan, Paul D.
AU - Lake, Douglas F.
AU - Tibes, Raoul
AU - Lee, Jeong Heon
AU - Choi, Jeong Hyeon
AU - Ho, Thai H
AU - Robertson, Keith D
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - DNA methylation
KW - Epigenetics
KW - Histone methylation
KW - Renal cell cancer
KW - SETD2
UR - http://www.scopus.com/inward/record.url?scp=84957655787&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957655787&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.6481
DO - 10.18632/oncotarget.6481
M3 - Article
C2 - 26646321
AN - SCOPUS:84957655787
VL - 7
SP - 1927
EP - 1946
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 2
ER -