E-MTAB-1936 - Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects
Released on 17 October 2013, last updated on 2 May 2014
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 chromatin landscape and transcriptional program in ccRCC or other cancers is not understood. Here, we identified alterations in chromatin organization and transcript profiles 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. Additional file: MutationAnnotation.txt- contains sample ID, location of variant on hg19, reference allele, alternate allele, reference depth, alternate depth, frequency, confidence score, gene symbol, mutation type, mutation location (transcript ID and exon number, if applicable), and amino acid change.
ChIP-seq, RNA-seq of coding RNA, RNA-seq of non coding RNA, genotyping by high throughput sequencing, FAIRE-Seq, co-expression, disease state design, genotype design, in vivo
Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Jeremy M. Simon, Kathryn E. Hacker, Darshan Singh, A. Rose Brannon, Joel S. Parker, Matthew Weiser, Thai H. Ho, Pei-Fen Kuan, Eric Jonasch, Terrence S. Furey, Jan F. Prins, Jason D. Lieb, W. Kimryn Rathmell, and Ian J. Davis.