The interplay between DNA and histone methylation: molecular mechanisms and disease implications

Abstract

Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome-wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA- and histone-modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.

Keywords: DNA methylation; cancer; chromatin; developmental disorder; histone methylation.

Figure 1. Interaction between DNMT1/UHRF1 and histone methylation during maintenance DNA methylation

(A) In the absence of chromatin interaction, UHRF1 adopts a closed conformation, where the linker region between SRA and RING domains binds to the TTD domain and the SRA domain binds to PHD finger. Upon engagement with histone and hemi‐methylated DNA, inter‐domain conformational change will enable the TTD‐PHD module to recognize H3K9me3 and H3R2, and SRA domain to bind to hemi‐methylated DNA. This open conformation will facilitate the ubiquitination of histone H3K18 and H3K23 by UHRF1, which in turn recruits DNMT1 to catalyze maintenance DNA methylation. (B) Schematics summarizing the functional impact of various domain‐inactivating UHRF1 missense mutations on maintenance DNA methylation or re‐methylation following global demethylation. (C) Recent study suggests two distinct modes of maintenance methylation by DNMT1‐UHRF1. At the replication fork, interactions between DNMT1 and PCNA, and UHRF1‐TTD and methylated LIG1, facilitate replication‐coupled maintenance methylation. The interaction between UHRF1‐TTD and H3K9me3, on the other hand, facilitates replication‐uncoupled maintenance methylation.

Figure 2. Various mechanisms underlying targeting of de novo DNMTs by histone methylation

(A) At promoters of actively transcribing genes, high levels of H3K4me3 oppose ADD domain and the binding of DNMT3L‐DNMT3A/B to prevent de novo CpG methylation. (B) At gene bodies of actively transcribing genes, high levels of H3K36me3 interact with PWWP domain of DNMT3B and facilitate its genic localization. (C) A parallel pathway operates at the intergenic region, where H3K36me2 interacts with PWWP domain of DNMT3A and facilitates its intergenic localization. (D) At repetitive elements and retrotransposons, interactions between H3K9 methyltransferases and DNMT3A/B enable co‐localization of H3K9me3 and CpG methylation for transcriptional silencing.

Figure 3. Dysregulated interplay between DNA and histone methylation in human OGID syndromes

During normal development, H3K36me2 facilitates the deposition of CpG methylation by recruiting DNMT3A at euchromatic intergenic regions, and these two modifications act together to antagonize PRC2 and H3K27me3. In Soto syndrome, NSD1 mutations and deletions lead to reduced H3K36me2 and CpG methylation, and a resulting gain of H3K27me3. In TBRS, loss‐of‐function mutations in DNMT3A reduce CpG methylation, although its impact on H3K36me2 and H3K27me3 is unclear. Some Weaver syndrome patients carry missense mutation of EZH2 (e.g., K634E) that renders the PRC2 insensitive to inhibition by H3K36 methylation, which could potentially leads to accumulation of H3K27me3 at intergenic regions despite the presence of H3K36me2. The significant overlap in clinical features of Soto, Weaver, and TRBS patients suggests that an imbalance of H3K36me2, H3K27me3, and CpG methylation could represent a common pathogenic mechanism.

Figure 4. Reprogramming of DNA methylation during cancer progression

The transition from normal to cancerous state is associated with changes in genome‐wide patterns of DNA methylation. While promoter CpG islands of active genes marked by H3K4me3 remain free of DNA methylation, polycomb‐regulated promoter CpG islands become hypermethylated, possibly due to aberrant targeting of DNMT3A/B through an unknown mechanism. The gene‐poor, H3K9 methylation‐rich, late‐replicating lamina‐associated domains undergo progressive loss of maintenance methylation during cancer cell replication. Gene body and intergenic regions marked by H3K36 methylation are protected from such mitotically linked DNA hypomethylation, presumably due to the preferential targeting and activity of de novo methyltransferases DNMT3A/B.