High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma

Thai H Ho, I. Y. Park, H. Zhao, P. Tong, M. D. Champion, Huihuang D Yan, F. A. Monzon, A. Hoang, P. Tamboli, Alexander Parker, Richard W Joseph, W. Qiao, K. Dykema, N. M. Tannir, Erik P Castle, R. Nunez-Nateras, B. T. Teh, J. Wang, C. L. Walker, M. C. HungE. Jonasch

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.221.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jun 15 2015

Fingerprint

Renal Cell Carcinoma
Histones
Lysine
Neoplasm Metastasis
Kidney
Genome
RNA Splicing
RNA Sequence Analysis
High-Throughput Nucleotide Sequencing
Cell Line
Neoplasms
Atlases
Chromatin Immunoprecipitation
Alternative Splicing
Methyltransferases
Nephrectomy
Oncogenes
Epigenomics
Publications
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma. / Ho, Thai H; Park, I. Y.; Zhao, H.; Tong, P.; Champion, M. D.; Yan, Huihuang D; Monzon, F. A.; Hoang, A.; Tamboli, P.; Parker, Alexander; Joseph, Richard W; Qiao, W.; Dykema, K.; Tannir, N. M.; Castle, Erik P; Nunez-Nateras, R.; Teh, B. T.; Wang, J.; Walker, C. L.; Hung, M. C.; Jonasch, E.

In: Oncogene, 15.06.2015.

Research output: Contribution to journalArticle

Ho, TH, Park, IY, Zhao, H, Tong, P, Champion, MD, Yan, HD, Monzon, FA, Hoang, A, Tamboli, P, Parker, A, Joseph, RW, Qiao, W, Dykema, K, Tannir, NM, Castle, EP, Nunez-Nateras, R, Teh, BT, Wang, J, Walker, CL, Hung, MC & Jonasch, E 2015, 'High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma', Oncogene. https://doi.org/10.1038/onc.2015.221
Ho, Thai H ; Park, I. Y. ; Zhao, H. ; Tong, P. ; Champion, M. D. ; Yan, Huihuang D ; Monzon, F. A. ; Hoang, A. ; Tamboli, P. ; Parker, Alexander ; Joseph, Richard W ; Qiao, W. ; Dykema, K. ; Tannir, N. M. ; Castle, Erik P ; Nunez-Nateras, R. ; Teh, B. T. ; Wang, J. ; Walker, C. L. ; Hung, M. C. ; Jonasch, E. / High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma. In: Oncogene. 2015.
@article{2747fb1182874596bfd6e9670410a994,
title = "High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma",
abstract = "Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90{\%}), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20{\%} in primary ccRCC (90{\%} positive nuclei in uninvolved vs 70{\%} positive nuclei in ccRCC) and reduced by ~60{\%} in metastases (90{\%} positive in uninvolved kidney vs 30{\%} positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.221.",
author = "Ho, {Thai H} and Park, {I. Y.} and H. Zhao and P. Tong and Champion, {M. D.} and Yan, {Huihuang D} and Monzon, {F. A.} and A. Hoang and P. Tamboli and Alexander Parker and Joseph, {Richard W} and W. Qiao and K. Dykema and Tannir, {N. M.} and Castle, {Erik P} and R. Nunez-Nateras and Teh, {B. T.} and J. Wang and Walker, {C. L.} and Hung, {M. C.} and E. Jonasch",
year = "2015",
month = "6",
day = "15",
doi = "10.1038/onc.2015.221",
language = "English (US)",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma

AU - Ho, Thai H

AU - Park, I. Y.

AU - Zhao, H.

AU - Tong, P.

AU - Champion, M. D.

AU - Yan, Huihuang D

AU - Monzon, F. A.

AU - Hoang, A.

AU - Tamboli, P.

AU - Parker, Alexander

AU - Joseph, Richard W

AU - Qiao, W.

AU - Dykema, K.

AU - Tannir, N. M.

AU - Castle, Erik P

AU - Nunez-Nateras, R.

AU - Teh, B. T.

AU - Wang, J.

AU - Walker, C. L.

AU - Hung, M. C.

AU - Jonasch, E.

PY - 2015/6/15

Y1 - 2015/6/15

N2 - Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.221.

AB - Mutations in SETD2, a histone H3 lysine trimethyltransferase, have been identified in clear cell renal cell carcinoma (ccRCC); however it is unclear if loss of SETD2 function alters the genomic distribution of histone 3 lysine 36 trimethylation (H3K36me3) in ccRCC. Furthermore, published epigenomic profiles are not specific to H3K36me3 or metastatic tumors. To determine if progressive SETD2 and H3K36me3 dysregulation occurs in metastatic tumors, H3K36me3, SETD2 copy number (CN) or SETD2 mRNA abundance was assessed in two independent cohorts: metastatic ccRCC (n=71) and the Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma data set (n=413). Although SETD2 CN loss occurs with high frequency (>90%), H3K36me3 is not significantly impacted by monoallelic loss of SETD2. H3K36me3-positive nuclei were reduced an average of ~20% in primary ccRCC (90% positive nuclei in uninvolved vs 70% positive nuclei in ccRCC) and reduced by ~60% in metastases (90% positive in uninvolved kidney vs 30% positive in metastases) (P<0.001). To define a kidney-specific H3K36me3 profile, we generated genome-wide H3K36me3 profiles from four cytoreductive nephrectomies and SETD2 isogenic renal cell carcinoma (RCC) cell lines using chromatin immunoprecipitation coupled with high-throughput DNA sequencing and RNA sequencing. SETD2 loss of methyltransferase activity leads to regional alterations of H3K36me3 associated with aberrant RNA splicing in a SETD2 mutant RCC and SETD2 knockout cell line. These data suggest that during progression of ccRCC, a decline in H3K36me3 is observed in distant metastases, and regional H3K36me3 alterations influence alternative splicing in ccRCC.Oncogene advance online publication, 22 June 2015; doi:10.1038/onc.2015.221.

UR - http://www.scopus.com/inward/record.url?scp=84930988861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930988861&partnerID=8YFLogxK

U2 - 10.1038/onc.2015.221

DO - 10.1038/onc.2015.221

M3 - Article

C2 - 26073078

AN - SCOPUS:84930988861

JO - Oncogene

JF - Oncogene

SN - 0950-9232

ER -