Jason Lieb

Jason 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 Singh^2,4, A. Rose Brannon^1,3, Joel S. Parker^1,3, Matthew Weiser^1,2, Thai H. Ho^{^}, Pei-Fen Kuan^3,6, Eric Jonasch⁵, Terrence S. Furey^1,3,7,8, 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