Chatting histone modifications in mammals

Abstract

Eukaryotic chromatin can be highly dynamic and can continuously exchange between an open transcriptionally active conformation and a compacted silenced one. Post-translational modifications of histones have a pivotal role in regulating chromatin states, thus influencing all chromatin dependent processes. Methylation is currently one of the best characterized histone modification and occurs on arginine and lysine residues. Histone methylation can regulate other modifications (e.g. acetylation, phosphorylation and ubiquitination) in order to define a precise functional chromatin environment. In this review we focus on histone methylation and demethylation, as well as on the enzymes responsible for setting these marks. In particular we are describing novel concepts on the interdependence of histone modifications marks and discussing the molecular mechanisms governing this cross-talks.

Figure 1:

Mechanisms of cross-talk between histone modifications. (A) Cross-talk in cis; acetylation of H3K18 and H3K23 by CBP can promote the methylation of H3R17 by the methyltransferase CARM1, resulting in activation of estrogene-responsive genes [90]. (B) Cross-talk in trans; H2BK120 ubiquitination by RAD6 is recognized by the WDR82 subunit of the SET1A/B COMPASS complex and it is a prerequisite for efficient H3K4 methylation by SET1A/B and transcriptional activation of target genes in mammals. (C) Multifunctional histone modifications complexes, simplified model of PRC complex function; in Drosophila the Polycomb repressive complexes PRC1, PRC2 and PhoRC are recruited to chromatin in a hierarchical manner and they coordinate distinct histone modifications. The Pho subunit of PhoRC complex binds specific PRE (Polycomb responsive element) elements in the DNA. The PRC2 complex is recruited to this PRE via interactions between the Pho protein and E(Z) (drosophila homolog of human EZH2), the methyltarnsferase subunit of the PRC2 complex. E(Z), methylates H3K27 forming a binding site for PC, a subunit of the PRC1 complex. dRING, the E3 ligase within the PRC2 complex can mediate ubiquitination of H2AK119. dRING is also a subunit of the dRAF (dRING associated factors), an additonal Polycomb complex in Drosophila. dRAF contains the histone demethylase KDM2, which coordinates removal of H3K36me3 with stimulation of H2AK119 ubiquitination by dRING. dRAF cooperates with PRC1 in gene silecing by Polycomb complexes. Additionally non-coding RNAs had recently been implicated in the trageting of Polycomb complexes (not shown).

Figure 2:

Cross-talk between H3 methylation and phosphorylation in AR-dependent transcriptional regulation. Top panel: in the absence of ligand, the androgen-receptor (AR) is present in the cytoplasma and AR-regulated genes are silenced by the presence of H3K9 methylation. PKCβ1, LSD1 and JMJD2C are already present on chromatin. Bottom panel: association of ligand-activated AR with PRK1 leads to activation of PKCβI. Phosphorylation of H3T6 by activated PKCβI prevents LSD1 from demethylating H3K4me2/me1 (dashed black arrow) but not H3K9me2/me1 and AR-dependent genes get activated. In addition, PRK1 phosphorylates H3T11. This mark enhances JMJD2C demethylating activity for H3K9me3 further contributing to transcriptional activation. The PKCβ1 mediated pathway is indicated by black arrows. The PRK1 mediated pathway is indicated by red arrows. A colour version of this figure is available at http://bfg.oxfordjournals.org/.