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.

Architecture and evolution of subtelomeres in the unicellular green algaChlamydomonas reinhardtii

“…To investigate chromatin modification at C. reinhardtii subtelomeres, we analysed methylation of cytosines (5-methylcytosines, 5mC) in CpG contexts, an epigenetic mark primarily associated with transcriptional silencing ( 83 ), detected directly from the Nanopore sequencing reads using DeepSignal, a deep-learning-based method ( 77 ). We first confirmed that this method was able to detect regions within previously identified hypermethylated loci ( 84 ), characterised by the most common element L1-1_CR (also known as ZeppL-1_cRei ) which was recently shown to be the major constituent repeat of centromeres ( 64 ) ( Supplemental Figure S6A ).…”

“…DNA and histone methylation cooperate to specify the epigenetic landscape ( 83 ). Consistent with the detection of 5mC at most subtelomeres, Strenkert et al.…”

NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer

“…DNMT3B colocalizes selectively with H3K36me3 and methylates active gene bodies to enhance gene expression. DNMT3A binds more strongly to H3K36me2 than to H3K36me3 and preferentially methylates intergenic chromatin, which often co-occurs with PRC2-mediated H3K27me2 as well as NSD1-mediated-H3K36me2 [ 30 , 31 ]. Functional studies in ES cells revealed that ablation of NSD1 results in redistribution of DNMT3A to H3K36me gene bodies and reduced methylation of intergenic DNA [ 32 ].…”

Structure, Activity and Function of the NSD3 Protein Lysine Methyltransferase

“…These were shown to mediate binding of NSD1 to methylated H3K4 and K9 with a preference for dimethylated lysines in vitro [ 21 ]. Only the PHD4, PHD5 and C4HCH domains show binding to both modifications, which is controversial as both methylation states are associated with opposite transcriptional states [ 29 , 30 , 31 ]. The binding of various states of H3K4 and H3K9 methylation would allow NSD1 to recognize genes in stages of transcriptional activation and repression.…”

“…The hydrophobic side chain of the lysine points towards the methyl donor S-adenosylmethionine (SAM) through insertion into a hydrophobic pocket. [ 30 ]. The structures currently available for the NSD family show that a loop connecting the SET and post-SET domains can adopt multiple conformations, which are important for the regulation of the catalytic activity.…”