The interplay of histone modifications - writers that read

Abstract

Histones are subject to a vast array of posttranslational modifications including acetylation, methylation, phosphorylation, and ubiquitylation. The writers of these modifications play important roles in normal development and their mutation or misregulation is linked with both genetic disorders and various cancers. Readers of these marks contain protein domains that allow their recruitment to chromatin. Interestingly, writers often contain domains which can read chromatin marks, allowing the reinforcement of modifications through a positive feedback loop or inhibition of their activity by other modifications. We discuss how such positive reinforcement can result in chromatin states that are robust and can be epigenetically maintained through cell division. We describe the implications of these regulatory systems in relation to modifications including H3K4me3, H3K79me3, and H3K36me3 that are associated with active genes and H3K27me3 and H3K9me3 that have been linked to transcriptional repression. We also review the crosstalk between active and repressive modifications, illustrated by the interplay between the Polycomb and Trithorax histone-modifying proteins, and discuss how this may be important in defining gene expression states during development.

Keywords: Polycomb; Trithorax; chromatin; histone modifications.

Figure 1. The distribution of histone modifications over active and repressed genes

Figure 2. Crosstalk between chromatin writers and histone marks at active and repressed genes

Chromatin writers and chromatin marks associated with active genes positively reinforce each other through various positive feedback mechanisms. The same holds true for writers and marks associated with repressed genes. Additionally, negative feedback mechanisms and mutual inhibition between writers and marks associated with the opposite gene expression state also reinforce distinct transcriptional states.

Figure 3. Establishment of H3K4me3 and interplay with H2BK120u1

The SETD1 complex associates with Pol II, and H3K4me3 is deposited co-transcriptionally. CFP1 (associated with SETD1) and MLL1/2 can be recruited to promoters de novo via CxxC domain binding to CpG islands. H2BK120u1 can recruit H3K4 writers, possibly through recognition of H2BK120u1 by the ASH2L subunit.

Figure 4. Interplay between H3K4me3, H3K36me3, and H3/H4 acetylation

H3K4me3 reinforces H3 and H4 acetylation at the promoters of active genes. Various H3K36 writers catalyze H3K36me1/2 and SETD2 associates with elongating Pol II and catalyzes H3K36me3 co-transcriptionally. H3K36me2/3 recruits HDACs that deacetylate histones over gene bodies.

Figure 5. Crosstalk between the Polycomb complexes PRC1 and PRC2

PRC2 reinforces its own mark through binding of EED to H3K27me3. PRC1 may also reinforce its own mark through binding of RYBP to H2AK119u1. Establishment of PRC1 can be reinforced by the presence of PRC2, through recognition of H3K27me3 by the CBX subunit of PRC1. PRC2 establishment can also be reinforced by PRC1 through the recognition of H2AK119u1 by the JARID2/AEBP2 PRC2.2 complex.

Figure 6. Interplay between H3K9me3, DNA methylation, and H3K27me3

(A) At the pericentric heterochromatin, DNA methylation and H3K9me3 positively reinforce each other. HP1 binds H3K9me3 and recruits the de novo DNA methyltransferases DNMT3A/B. MECP2 can bind methylated DNA and recruit the H3K9me3 methyltransferase SUV3-9. (B) H3K27me3 and H3K9me2 coexist on the inactive X chromosome. CDYL may recruit G9a to the inactive X chromosome through its ability to recognize H3K9me2 and H3K27me3. CDYL may reinforce the propagation of H3K9me2 at the Xi.