Cross-talk between Histone Modifications in Response to Histone Deacetylase Inhibitors

Abstract

Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the "degree" of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.A growing body of evidence suggests that many different types of post-translational histone modifications play key roles in regulating gene expression and that some modifications at least are functionally inter-related (1). The linked deposition of distinct modifications can occur both on the same histone tail, e.g. H3S10 phosphorylation and H3K9 acetylation (2) or on different tails, e.g. H2A ubiquitination and H3 methylation (3), histone acetylation, and methylation (4, 5). Multiprotein complexes have been identified that are capable of depositing, or removing, different modifications in a coordinated manner (e.g. histone demethylase and deacetylase activity in coREST) (6). Similarly, binding proteins are sensitive to combinations of modifications; for example, HP1 binding to the H3 tail requires histone H3K9 methylation but is blocked by H3S10 phosphorylation and H3K14 acetylation (Ref. 7, although see Ref. 8).This suggests that epigenetic marks are not deposited or recognized in isolation but comprise a complex and inter-related collection of modifications at adjacent residues.The correlation between different histone modifications is particularly clear for histone H3 acetylation and the methylation of histone H3 lysine 4 (H3K4me). Mass spectrometric analysis of the cellular pool of histones indicates that this methyl mark is associated with histone H3 molecules containing high levels of acetylation (9). This is consistent with the observed co-localization of these marks, which show related distribution patterns both at a chromosome-wide level during X inactivation (10) and over the coding regions of individual genes (11,12). These correlations may arise due to physical links between histone-modifying enzymes such that they are co-recruited to the same loci. Both MLL1, a histone methyltransferase (HMT) 2 that can generate H3K4me marks (13), and Chd1, the chromatin remodeler that is subsequently recruited by this methyl mark, associate with histone acetyltransferase activities (14, 15), whereas the LSD1 complex that removes some of these methyl marks contains the histone deacetylases HDAC1 and HDAC2 (16). However, the interaction could also arise ...

A Genome-Wide Chronological Study of Gene Expression and Two Histone Modifications, H3K4me3 and H3K9ac, during Developmental Leaf Senescence

“…These data suggest that H3K9ac modifications are present before H3K4 trimethylation for the K4-SURGs. In animal systems, evidence supporting K4 trimethylation of acetylated H3 has been published (Bradbury et al, 2005;Nightingale et al, 2007;Taverna et al, 2007), and it is possible that the H3K9 acetylation serves as a template for the gain of H3K4me3 marks during leaf senescence.…”

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

“…Interestingly, entinostat also had an effect upon trimethylation of H3K4. Other HDAC inhibitors like PB, VPA (Nightingale et al, 2007) and trichostatin A (Paul et al, 2010) have been described to induce trimethylation of H3K4, suggesting a functional link between histone acetylation and histone methylation. The group of Constanze Bonifer described the interaction between AML1 (RUNX1) and the initiation of chromatin remodeling through trimethylation of H3K4 in pluripotent hematopoietic precursors cells, suggesting that Epigenetic regulation of LAT2 by AML1/ETO J Duque-Afonso et al the epigenetic changes of AML1/ETO target promoters may be due to modification not only in histone acetylation but also in histone methylation (Hoogenkamp et al, 2009).…”

E2F-associated chromatin modifiers and cell cycle control

“…It is catalyzed by histone methyltransferases (HMTs) of the mixed lineage leukemia (MLL) and SET families and is thought to be influenced by the degree of acetylation of histone H3 [23]. Once more, a persistent challenge in this field is to discover how gene-specific recruitment of these chromatin modifying enzymes is achieved.…”