Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects
- Jeremy M. Simon1,
- Kathryn E. Hacker1,
- Darshan Singh1,
- A. Rose Brannon2,
- Joel S. Parker1,
- Matthew Weiser1,
- Thai H. Ho3,
- Pei-Fen Kuan1,
- Eric Jonasch4,
- Terrence S. Furey1,
- Jan F. Prins1,
- Jason D. Lieb1,
- W. Kimryn Rathmell1 and
- Ian J. Davis1,5
- 1 University of North Carolina at Chapel Hill;
- 2 Memorial Sloan-Kettering Cancer Center;
- 3 Mayo Clinic Scottsdale;
- 4 MD Anderson Cancer Center
- ↵* Corresponding author; email: ian_davis{at}med.unc.edu
Abstract
Comprehensive sequencing of human cancers has identified recurrent mutations in genes encoding chromatin regulatory proteins. For clear cell renal cell carcinoma (ccRCC), three of the five commonly mutated genes encode the chromatin regulators PBRM1, SETD2, and BAP1. How these mutations alter the genomic landscape in ccRCC or other cancers is not understood. Here, we identified alterations in chromatin organization and transcription associated with mutations in chromatin regulators in a large cohort of primary human kidney tumors. By associating variation in chromatin organization with mutations in SETD2, which encodes the enzyme responsible for H3K36 trimethylation, we found that changes in chromatin accessibility occurred primarily within actively transcribed genes. This increase in chromatin accessibility was linked with widespread alterations in RNA processing, including intron retention and aberrant splicing, affecting approximately 25% of all expressed genes. Further, decreased nucleosome occupancy proximal to misspliced exons was observed in tumors lacking H3K36me3. These results directly link mutations in SETD2 to chromatin accessibility changes and RNA processing defects in cancer. Detecting the functional consequences of specific mutations in chromatin regulatory proteins in primary human samples could ultimately inform the therapeutic application of an emerging class of chromatin-targeted compounds.
- Received March 29, 2013.
- Accepted October 10, 2013.
- Published by Cold Spring Harbor Laboratory Press
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