Histone Lysine Methylation Pathway

Pathway Description:

The nucleosome is the primary building block of chromatin containing a histone octamer composed of two sets of H3-H4 and H2A-H2B dimers. Originally thought to function as a static scaffold for DNA packaging, histones have more recently been shown to be dynamic proteins, undergoing multiple types of post-translational modifications and impacting numerous nuclear functions. Lysine methylation is one such modification and is a major determinant for genome organization and the formation of active and inactive regions of the genome. Lysines can have three different methylation states (mono-, di-, and tri-) that are associated with different nuclear features and transcriptional states. In order to establish these methylation states, cells have enzymes that both add (lysine methyltransferases- KMTs) and remove (lysine demethylases- KDMs) different degrees of methylation from specific lysines within the histones. To date, all but one histone lysine methyltransferase (DOT1L/KMT4) has a conserved catalytic SET domain that was originally identified in the Drosophila Su[var]3-9, Enhancer of zeste, and Trithorax proteins. In the case of the histone lysine demethylases, there are two different classes: the FAD-dependent amine oxidases and the JmjC-containing enzymes. Both KMTs and KDMs have specificity for specific lysine residues and degrees of methylation within the histone tails. Therefore, all KMTs and KDMs are not the same in their biological functions or roles in transcriptional output.

Lysine methylation has been implicated in both transcriptional activation (H3K4, K36, K79) and silencing (H3K9, K27, H4K20). The degree of methylation is associated with different outcomes. For example, H4K20 monomethyation (H4K20me1) is observed in the bodies of active genes, while H4K20 trimethylation (H4K20me3) is affiliated with gene repression and compacted genomic regions. Gene regulation is also affected by the location of the methylated lysine residue with respect to the DNA sequence. For example, H3K9me3 at promoters is associated with gene repression, while some induced genes have H3K9me3 in the gene body. Since this modification is uncharged and chemically inert, the impact these modifications have is through recognition by other proteins with binding motifs. Lysine methylation coordinates the recruitment of chromatin modifying enzymes. Chromodomains (e.g., found in HP1, PRC1), PHD fingers (e.g., found in BPTF, ING2, SMCX/KDM5C), Tudor domains (e.g., found in 53BP1 and JMJD2A/KDM4A), PWWP domains (e.g., found in ZMYND11) and WD-40 domains (e.g., found in WDR5) are among a growing list of methyl lysine binding modules found in histone acetyltransferases, deacetylases, methylases, demethylases and ATP-dependent chromatin remodeling enzymes. Lysine methylation provides a binding surface for these enzymes, which then regulate chromatin condensation and nucleosome mobility, active and inactive transcription as well as DNA repair and replication. In addition, lysine methylation can block binding of proteins that interact with unmethylated histones or directly inhibit catalysis of other regulatory modifications on neighboring residues.

Histone methylation is crucial for proper programming of the genome during development and misregulation of the methylation machinery can lead to diseased states such as cancer. In fact, cancer genome analyses have uncovered lysine mutations in H3K27 and H3K36. These sites are enriched in subsets of cancer. Therefore, an entirely new therapeutic and biomarker space is emerging with the discovery of these enzymes, the impact modifications have on the genome and disease associated mutations.

Selected Reviews:

Black JC, Van Rechem C, Whetstine JR (2012) Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell 48(4), 491–507.

Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13(5), 343–57.

Herz HM, Garruss A, Shilatifard A (2013) SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 38(12), 621–39.

Kooistra SM, Helin K (2012) Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 13(5), 297–311.

Tee WW, Reinberg D (2014) Chromatin features and the epigenetic regulation of pluripotency states in ESCs. Development 141(12), 2376–90.