Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects

  1. Ian J. Davis1,3,7,10,15,16
  1. 1Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  2. 2Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  3. 3Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  4. 4Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  5. 5Department of Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA;
  6. 6Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  7. 7Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  8. 8Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  9. 9Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
  10. 10Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina 27514, USA
    1. 14 These authors contributed equally to this work.

    2. 15 These authors contributed equally to this work.

    • Present addresses: 11Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA;

    • 12 Division of Hematology/Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ 85054, USA;

    • 13 Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, 144 Carl Icahn Laboratory, Princeton, NJ 08544, USA.

    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 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 ∼25% of all expressed genes. Furthermore, 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.

    Footnotes

    • Received March 29, 2013.
    • Accepted October 10, 2013.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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