title: Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects.
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.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27514, USA;
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hacker
authors.forename: Darshan
authors.initials: D
authors.lastname: Singh
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Matthew
authors.initials: M
authors.lastname: Weiser
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Kuan
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.forename: Terrence S
authors.initials: TS
authors.lastname: Furey
authors.forename: Jan F
authors.initials: JF
authors.lastname: Prins
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lieb
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D043222:Ubiquitin Thiolesterase