SummaryThe existence of different patterns of chemical modifications (acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation) of the histone tails led, some years ago, to the histone code hypothesis. According to this hypothesis, these modifications would provide binding sites for proteins that can change the chromatin state to either active or repressed. Interestingly, some protein domains present in histone-modifying enzymes are known to interact with these covalent marks in the histone tails. This was first shown for the bromodomain, which was found to interact selectively with acetylated lysines at the histone tails. More recently, it has been described that the chromodomain can be targeted to methylation marks in histone N-terminal domains. Finally, the interaction between the SANT domain and histones is also well documented. Overall, experimental evidence suggests that these domains could be involved in the recruitment of histone-modifying enzymes to discrete chromosomal locations, and/or in the regulation their enzymatic activity. Within this context, we review the distribution of bromodomains, chromodomains and SANT domains among chromatin-modifying enzymes and discuss how they can contribute to the translation of the histone code. The histone code hypothesis The packing of the eukaryotic genome into chromatin provides the means for compaction of the entire genome inside the nucleus. However, this packing restricts the access to DNA of the many regulatory proteins essential for biological processes like replication, transcription, DNA repair and recombination.(1)There are two mechanisms that can counterbalance the repressive nature of chromatin, allowing access to nucleosomal DNA: (i) covalent modification of histone tails like acetylation, methylation, phosphorylation and ubiquitination; (2)(3)(4)(5) and (ii) altering of the nucleosomal structure by enzymes utilising energy from ATP hydrolysis.In the early nineties, it was proposed that histone covalent modifications can work as recognition signals, directing the binding to chromatin of non-histone proteins that determine chromatin function. (7,8) More recently, it has been hypothesized that specific tail modifications and/or their combinations constitute a code, the histone code, that determines the transcriptional state of the genes. (9)(10)(11) According to this hypothesis, ''multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple tails, specify unique downstream functions''.In the last years, an increasing amount of experimental data has provided clear support for the different aspects of the histone code hypothesis, contributing to refine and improve it.(For review 12,13) One important point that has been addressed by different authors is the idea that the histone code must use combinations of modifications.(9) For example, H3 methylated at K9 could initiate chromatin condensation and silencing (14,15) but, in the context of methylated H3K4 and H4K20, methyl-K9 H3 helps to maintain ...