Histone H3 tail trimethylated at Lysine 4 and Lysine 36 (H3K4me3-H3K36me3) (H3K4me3-H3K36me3)

Histone H3 is a core protein within the nucleosome, and its N-terminal tail undergoes extensive post-translational modifications that regulate chromatin accessibility and gene expression (UniProt P68431). The specific combination of trimethylation at Lysine 4 (H3K4me3) and Lysine 36 (H3K36me3) is a hallmark of transcriptionally active chromatin, where H3K4me3 typically marks active promoters and H3K36me3 marks the gene body during transcription elongation (Santos-Rosa et al., 2002; Kizer et al., 2005). This dual-mark signature acts as a scaffold for the recruitment of "reader" proteins, such as those containing PHD fingers or chromodomains, which facilitate the assembly of transcriptional machinery (Wang et al., 2009). In various malignancies, particularly acute myeloid leukemia (AML) and certain solid tumors, the regulation of these marks is subverted by mutations in "writer" enzymes like MLL1 (KMT2A) or "eraser" enzymes, leading to the aberrant activation of oncogenes (Issa et al., 2023). Therapeutic intervention strategies involve small molecules that disrupt the binding of reader proteins to these methylated residues or inhibit the methyltransferases responsible for their deposition. Consequently, this histone tail configuration serves as a critical focal point for epigenetic drug discovery aimed at restoring normal gene expression patterns in cancer cells.

Other names

H3K4me3-H3K36me3Histone H3K4me3/H3K36me3Trimethylated Histone H3 (K4 and K36)Active chromatin signatureBivalent H3K4me3/H3K36me3 tail

Inhibition of the interaction between histone reader proteins (e.g., Menin, WDR5) and the methylated histone H3 tail, or inhibition of the methyltransferase enzymes (e.g., MLL1, SETD2) that catalyze these modifications.