FIGURE 3.

(A) Schematic representation of KDM5 interactions with chromatin. The catalytic composite JmjN/C domain binds the substrate H3 tail harboring methylated H3K4 (depicted as H3K4me3 for simplicity). Two of the PHD domains, PHD1 and 3, were shown to interact with unmethylated and trimethylated H3K4, respectively. The ARID domains are known DNA binding domains with a role in KDM5 chromatin targeting. How DNA binding is mediated in the context of full-length KDM5 proteins is currently unknown, since the arrangement of JmjC and ARID domains seems to be incompatible with the binding of nucleosomal DNA, according to homology models (Horton et al., 2016). The roles and potential chromatin interactions of the C5HC2 and PHD2 Zn fingers are unknown. Note that the depiction of three nucleosomes was chosen for clarity. It is not known how many nucleosomes are bound by a single KDM5 protein simultaneously. (B) Functional KDM5 interactions on chromatin. So far, only the binding of unmethylated H3K4 has been shown to regulate the demethylase activity of KDM5s. Given the potential interactions with HDACs, a direct or indirect responsiveness to other histone PTMs such as acetylated lysines, is conceivable. KDM5 proteins are recruited by transcription factors (TFs), reader domain proteins, or mediated by the association with other epigenetic regulators such as HDAC complexes or PRC2. The interaction and functional interplay of KDM5s with HDAC complexes and PRC2 suggests a potential mutual regulation of demethylase and other chromatin modifying activities. Such a direct interplay remains to be demonstrated experimentally.