Discovery of new chemical probes for the MRG15 chromo domain.

Methylation of histone tails represents a crucial post-translational modification involved in transcriptional regulation. An increasing body of evidence suggests that individual histone modifications, or a combination of them, may serve as a platform to recruit specific “reader” proteins, which then determine the transcriptional outcome of the target genes. In particular, methylated histone tails are recognized by chromatin-reading modules such as Chromo, Tudor, PWWP and MBT domains, together designated as the “Royal family” of chromatin binding domains. Among them, MRG15 (MORF Related Gene in chromosome 15, Figure 1), is a conserved chromodomain-containing nuclear protein that specifically binds to Lys36-methylated histone H3. Although several lines of evidence suggest that MRG15 and its related proteins are involved in gene regulation and DNA-repair processes, the mechanisms are still unknown. Being interested in the development of novel small molecule modulators of epigenetic targets, here we report the identification of the first class of inhibitors of MRG15, that might be new tools to study the function of MRG15 endogenously.