Histone H3 lysine 36 trimethylation (H3K36me3)

Histone H3 lysine 36 trimethylation (H3K36me3) is a pivotal epigenetic post-translational modification found on the tail of the histone H3 protein. It is predominantly deposited by the SET domain-containing protein 2 (SETD2) methyltransferase during the elongation phase of transcription, marking the gene bodies of actively transcribed regions. This modification is essential for maintaining genomic integrity, as it recruits key DNA repair factors such as RAD51 to sites of damage and prevents the initiation of cryptic transcription within gene bodies. Additionally, H3K36me3 serves as a recruitment signal for various 'reader' proteins that regulate alternative splicing and chromatin structure. In clinical oncology, the loss of H3K36me3—frequently caused by mutations in the SETD2 gene—is a defining characteristic of clear cell renal cell carcinoma (ccRCC) and certain high-grade pediatric gliomas, where it correlates with increased genomic instability and poor patient prognosis. Although the modification itself is not a druggable protein, it is a primary focal point for therapeutic intervention. Current strategies involve the use of histone demethylase (KDM) inhibitors to restore H3K36me3 levels or the application of PARP and WEE1 inhibitors to exploit the DNA repair defects inherent in H3K36me3-deficient tumors. Consequently, monitoring H3K36me3 status is increasingly used as a biomarker for patient stratification and to guide the use of precision epigenetic therapies.

Other names

H3K36me3Trimethylated histone H3 lysine 36H3K36 trimethylationHistone H3 trimethyl Lys36

Modulation of H3K36me3 levels typically occurs through the inhibition of histone demethylases (such as KDM4 family members) to prevent the removal of the methyl group, or by exploiting synthetic lethal vulnerabilities (e.g., PARP inhibition) in cells that have lost the mark due to SETD2 mutations.