Chromatin Density Matters
Histone methylation mediated by polycomb repressive complex 2 (PRC2) is involved in numerous biological processes, including cell differentiation, proliferation, and stem cell plasticity. Enhancer of Zeste homolog 2 (Ezh2), a subunit of PRC2, is a histone methyltransferase that specifically methylates histone H3 on lysine 27 (H3K27) and regulates polycomb gene silencing. In a recent study, Yuan et al. suggested that PRC2 activity is regulated by the density of the substrate chromatin.
The authors discovered that PRC2 had higher enzyme activity on dense oligonucleosomes relative to dispersed oligonucleosomes. Furthermore, PRC2 exhibited greater enzyme activity with dinucleosomes than with mononucleosomes and PRC2 activity was affected by the length of linker DNA as dinucleosomes with shorter linker DNA were better substrate for PRC2. The authors also showed that a fragment of histone H3 (amino acids 31 to 42) activated PRC2 enzyme activity but has no effect on other histone methyltransferases such as NSD2, Dot1L, Pr-Set7, and Suv4-20h1.
Bioinformatic analyses using results from published genome-wide nucleosome position profiles and chromatin immunoprecipitation sequencing (ChIP-seq) in human CD4+ T cells showed a negative correlation between the enrichment of PRC2-mediated histone modifications (such as dimethylated H3K27 and trimethylated H3K27) and nucleosome spacing. In agreement with the in vitro experiments, these data suggest that nucleosome density is a contributing factor in the distribution of PRC2-mediated histone modifications.
Previous studies reported that actively transcribed genes are resistant to PRC2 activity because they carry active marks (such as trimethylated H3K4, dimethylated H3K36, and trimethylated H3K36) that antagonize PRC2 activity. However, this may not be the only mechanism for PRC2 to maintain the inactive states of its target genes. Yuan et al. proposed that the PRC2 enzyme activity is prevented in these chromatin regions because these regions are less compact and with lower nucleosome density.
Histone modifications make a significant contribution to chromatin structure and chromatin density. Here, the authors showed that chromatin density is also an important contributor for histone modifications and demonstrate an interconnected relationship between chromatin modifications and nucleosomal density. So, what do you think came first, chromatin modifications or chromatin compaction?
Yuan et al. (2012) Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation. Science. 2012 Aug 24;337(6097):971-5.
Link to article: http://www.sciencemag.org/content/337/6097/971.abstract