Histone H3 and Histone H4 N-terminal tails (H3/H4 tails)

Histone H3 and H4 N-terminal tails are flexible, disordered regions of the core histone proteins that protrude from the nucleosome and serve as the primary site for post-translational modifications (PTMs) [1, 3]. These modifications, including acetylation, methylation, and phosphorylation, act as epigenetic marks that regulate chromatin structure and the recruitment of transcriptional machinery to specific genomic loci [1]. While the tails themselves are not typically the direct binding targets of small molecule drugs, they are the critical substrates for "writer" and "eraser" enzymes, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) [2, 4]. In many disease states, particularly cancer, these enzymes are inappropriately recruited to specific loci, leading to the deacetylation of H3 and H4 tails and the silencing of tumor suppressor genes [2]. Therapeutic strategies, such as the use of HDAC inhibitors (e.g., Vorinostat), aim to block these enzymes and restore the acetylation of histone tails at these recruited loci, thereby reactivating gene expression and inducing cell cycle arrest or apoptosis [2, 4].

Other names

Histone H3 tailsHistone H4 tailsN-terminal histone tailsH3/H4 N-terminiHistone H3 and H4 N-terminal domains

Inhibition of histone deacetylases (HDACs) leads to the accumulation of acetylated lysine residues on the H3 and H4 N-terminal tails, particularly at recruited genomic loci, which promotes an open chromatin structure and the reactivation of silenced genes [2, 4].