Characterization of structural variability sheds light on the specificity determinants of the interaction between effector domains and histone tails

Abstract

Structural characterization of the interaction between histone tails and effector modules (bromodomains, chromodomains, PHD fingers, etc.) is fundamental to understand the mechanistic aspects of epigenetic regulation of gene expression. In recent years many researchers have applied this approach to specific systems, thus providing a valuable but fragmentary view of the histone-effector interaction. In our work we use this information to characterize the structural features of the two main components of this interaction, histone peptides and the binding site of effector domains (focusing on those which target modified lysines), and increase our knowledge on its specificity determinants. Our results show that the binding sites of effectors are structurally variable, but some clear trends allow their classification in three main groups: flat-groove, narrow-groove and cavity-insertion. In addition, we found that even within these classes binding site variability is substantial. These results in context with the work from other researchers indicate that the there are at least two determinants of binding specificity in the binding site of effector modules. Finally, our analysis of the histone peptides sheds light on the structural transition experienced by histone tails upon effector binding, showing that it may vary depending on the local properties of the sequence stretch considered, thus allowing us to identify an additional specificity determinant for this interaction. Overall, the results of our analysis contribute to clarify the origins of specificity: different regions of the binding site and, in particular, differences in the disorder-order transitions experienced by different histone sequence stretches upon binding.

The histone demethylase PHF8 is a molecular safeguard of the IFNγ response

“…Importantly, deletions and point mutations in the PHF8 Jumonji-C (JmjC) catalytic domain lead to autistic spectrum disorders (ASDs) and Siderius-Hamel syndrome (22–27). In addition to the JmjC domain, PHF8 contains a PHD domain that recognizes and binds to nucleosomes trimethylated at lysine 4 in histone H3 (H3K4me3) and that are predominantly present at the transcription start site regions (TSS) of active promoters (28–33). H4K20me1 has been associated with both transcriptional activation and repression (16,34), highlighting the possibility that, in addition to being an activator, PHF8 could function as a transcriptional repressor.…”

RNA polymerase II progression through H3K27me3-enriched gene bodies requires JMJD3 histone demethylase

“…They are part of Polycomb repressive complex 2 (PRC2), which, together with the PRC1 complex, establishes the repressive state associated with H3K27me3 marks (Cao et al. , 2002; Lois et al. , 2010).…”

Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program

“…The enzymes responsible for this activity are enhancer of zeste homologs 1 and 2 (EZH1/2) (Cao et al, 2002;Czermin et al, 2002;Kuzmichev et al, 2002). H3K27me3 is recognized by the chromodomain of the polycomb protein that forms part of PRC1 (Cao et al, 2002;Lois et al, 2010). The recruitment of PRC1 leads to final transcriptional repression (Cao et al, 2002), a state that can be reversed by the removal of H3K27me3 marks by Jumonji C (JmjC) domain-containing proteins, JMJD3 and UTX histone demethylases (Agger et al, 2007;De Santa et al, 2007;Lan et al, 2007;Lee et al, 2007).…”