Alterations in chromatin accessibility and DNA methylation in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Clear cell renal cell carcinoma (ccRCC) involves genetic inactivation of chromatin remodeling enzymes.
• Epigenetic changes are crucial in cancer, but only DNA methylation is easily studied in clinical samples.
• A need exists to analyze other epigenetic modifications like chromatin accessibility in ccRCC.

Purpose of the Study:

• To adapt formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) for analyzing chromatin accessibility in clinical ccRCC samples.
• To compare chromatin accessibility with DNA methylation patterns in ccRCC.
• To identify specific regulatory elements and genes affected by altered chromatin accessibility in ccRCC.

Main Methods:

• Formaldehyde-assisted isolation of regulatory elements (FAIRE) procedure modified for small solid tumor samples.
• FAIRE combined with next-generation sequencing (FAIRE-seq) to map chromatin accessibility.
• Comparison of FAIRE-seq data with DNA methylation analysis.

Main Results:

• Chromatin accessibility decreases in many regions of the ccRCC epigenome, even where DNA methylation remains unchanged.
• FAIRE-seq successfully identified regulatory elements specific to normal and tumor tissues.
• Decreased chromatin accessibility was observed at key ccRCC-associated genes like PBRM1, SETD2, and MLL2.

Conclusions:

• The adapted FAIRE-seq method is effective for studying chromatin accessibility in small clinical ccRCC samples.
• Examining both chromatin accessibility and DNA methylation provides a more comprehensive understanding of ccRCC epigenome.
• These findings highlight the importance of epigenetic alterations in ccRCC pathogenesis and suggest potential therapeutic targets.