Jason Lieb

LiebJason D. Lieb
Professor of Molecular Biology
 And the Lewis-Sigler Institute for Integrative Genomics
Princeton University

Mutations in the H3K36 methyltransferase SETD2 link chromatin defects with aberrant RNA processing in human kidney cancer

Comprehensive sequencing of human cancers has identified recurrent mutations in genes encoding chromatin regulatory proteins, suggesting that chromatin maintenance is important for tumor suppression1. For clear cell renal cell carcinoma (ccRCC) three of the five genes mutated with a frequency above 5% encode the chromatin proteins PBRM1, SETD2, and BAP12-4. How the mutation of chromatin regulators affects cellular function in ccRCC or other cancers remains unknown. Here, we identify the functional genomic consequences of these mutations in a large cohort of primary human tumors. Tumor-specific chromatin differences occur at genes closely associated with Hypoxia-Inducible Factor (HIF) regulation, consistent with known oncogenic pathways in ccRCC. We link mutations in SETD2, the primary human histone H3K36 methyltransferase, with nucleosome loss in gene bodies. These defects occur primarily at genes normally marked by H3K36 methylation. We also show that tumors deficient in H3K36 methylation have widespread defects in RNA processing, including intron retention and aberrant splicing patterns. This direct link between defects in chromatin organization and aberrant cotranscriptional RNA processing suggests that deregulated transcript processing defines a subset of ccRCC. More generally, the results expand the consequences of chromatin defects in cancer to include RNA processing, and demonstrate a new potential mechanism of oncogenesis.

Authors and Affiliations:
Jeremy M. Simon*1,2,3, Kathryn E. Hacker*1,3, Darshan Singh2,4, A. Rose Brannon1,3, Joel S. Parker1,3, Matthew Weiser1,2, Thai H. Ho^, Pei-Fen Kuan3,6, Eric Jonasch5, Terrence S. Furey1,3,7,8, Jan F. Prins4, Jason D. Lieb**3,7,8, W. Kimryn Rathmell**1,3,9, and Ian J. Davis**1,3,7,10

1Department of Genetics, 2Curriculum in Bioinformatics and Computational Biology, 3Lineberger Comprehensive Cancer Center, 4Department of Computer Science, 6Department of Biostatistics, 7Carolina Center for Genome Sciences, 8 Department of Biology 9Department of Medicine, 10Department of Pediatrics, University of North Carolina, Chapel Hill, NC.  ^Department of Medical Oncology, MD Anderson Cancer Center, Houston, TX