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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Recurrent mutations in chromatin regulators are common in human cancers, including clear cell renal cell carcinoma (ccRCC).
• The functional impact of these mutations on chromatin and gene expression in ccRCC remains largely unknown.
• Key mutated genes in ccRCC include PBRM1, SETD2, and BAP1, all involved in chromatin regulation.

Purpose of the Study:

• To investigate how mutations in chromatin regulatory proteins alter chromatin organization and gene expression in primary human kidney tumors.
• To specifically link alterations in chromatin accessibility and RNA processing to mutations in SETD2 and its role in H3K36 trimethylation.

Main Methods:

• Analysis of chromatin organization and transcript profiles in a large cohort of primary human kidney tumors.
• Association of chromatin accessibility variations with mutations in SETD2.
• Examination of nucleosome occupancy near alternatively spliced exons in tumors with and without H3K36 trimethylation.

Main Results:

• Mutations in SETD2 were associated with increased chromatin accessibility, primarily within actively transcribed genes.
• Widespread alterations in RNA processing, including intron retention and aberrant splicing, were observed in approximately 25% of expressed genes.
• Tumors lacking H3K36 trimethylation (due to SETD2 mutations) showed decreased nucleosome occupancy near misspliced exons.

Conclusions:

• This study directly links SETD2 mutations to altered chromatin accessibility and RNA processing defects in ccRCC.
• Understanding these functional consequences in primary tumors can guide the development of chromatin-targeted cancer therapies.