Trimethyl Histone H4 Inhibitors

The term Trimethyl Histone H4 Inhibitors refers to a class of chemicals that influence the trimethylation status of histone H4, an epigenetic modification associated with chromatin structure and gene expression regulation. These inhibitors, while not directly targeting the trimethylation of H4, exert their effects on this process through the inhibition of various enzymes known as histone methyltransferases (HMTs) or by altering the activity of proteins that interact with or modify histone H4.

Histone H4 trimethylation is a dynamic and reversible post-translational modification that plays a crucial role in the epigenetic regulation of chromatin. Enzymes that add methyl groups to specific lysine residues on histone H4, such as the SUV39H1, are essential for the maintenance of heterochromatin and gene silencing. Inhibitors like chaetocin directly inhibit SUV39H1, thus reducing methylation at H4K20. Other HMT inhibitors, such as BIX-01294 and UNC0638, target the G9a and GLP enzymes, which primarily methylate histone H3 on lysine 9 (H3K9). However, the interplay between different histone modifications, known as the 'histone code', suggests that changes in methylation at one site can influence modifications at other sites, including H4 trimethylation. In addition to these, there are inhibitors such as DZNep, EPZ004777, EPZ-6438, GSK343, CPI-169, and EPZ015938 that target the enzyme EZH2, which is part of the Polycomb Repressive Complex 2 (PRC2) and is responsible for trimethylating histone H3 on lysine 27 (H3K27). Although these inhibitors primarily reduce H3K27me3, they can have downstream effects on the overall chromatin state that could affect histone H4 methylation indirectly. Similarly, inhibitors of other methyltransferases like SMYD2 (LLY-507) and the protein arginine methyltransferase (PRMT) family (MS023 and EPZ015666) can alter the wider histone modification landscape, leading to changes in H4 trimethylation.