The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer

Abstract

CpG methylation in transposons, exons, introns and intergenic regions is important for long-term silencing, silencing of parasitic sequences and alternative promoters, regulating imprinted gene expression and determining X chromosome inactivation. Promoter CpG islands, although rich in CpG dinucleotides, are unmethylated and remain so during all phases of mammalian embryogenesis and development, except in specific cases. The biological mechanisms that contribute to the maintenance of the unmethylated state of CpG islands remain elusive, but the modification of established DNA methylation patterns is a common feature in all types of tumors and is considered as an event that intrinsically, or in association with genetic lesions, feeds carcinogenesis. In this review, we focus on the latest results describing the role that the levels of H3K4 trimethylation may have in determining the aberrant hypermethylation of CpG islands in tumors.

LncRNA affects epigenetic reprogramming of porcine embryo development by regulating global epigenetic modification and the downstream gene SIN3A

“…In previous studies, H3K4me3 (Dahl et al, 2016) (Liu et al, 2016), H3K9me3 (Wang et al, 2018), and H3K27me3 (Liu et al, 2016) have been identified as epigenetic barriers during nuclear reprogramming in mice. In multicellular eukaryotes, H3K4me3 is predominantly localized at gene promoter regions, centered on the transcriptional start sites (Zardo, 2021). H3K4me3 deposited at the promoter-proximal and gene body regions facilitates transcription elongation and mRNA maturation (Foroozani et al, 2021).…”

“…DNA methylation is the earliest and most extensively studied epigenetic modification, which takes the CpG island as the central link (Zhou et al, 2021). Recent studies have indicated that methylation of CpG islands is related to the methylation status of H3K4 (Zardo, 2021), and the levels of methylated H3K4 (H3K4me3) tend to be inversely correlated with DNA methylation (Okitsu Cindy and Hsieh, 2007). DNA methylation is mainly established and maintained by DNA methyltransferases (DNMTs) that transfer a methyl group from S-adenyl methionine (SAM) to the fifth carbon of a cytosine residue to form 5mC (Zhou et al, 2021) (Chen and Zhang, 2020), while the active removal of methylation marks relies on the activity of ten-eleven translocation (TET) enzymes and thymine DNA glycosylase (TDG) (Parry et al, 2021).…”

IL-6 Promoter Hypomethylation Acts As a Diagnostic Biomarker in Hepatitis B Virus-Associated Hepatocellular Carcinoma

“…At the same time, based on logistic regression analysis, combined detection of IL-6 promoter methylation level and AFP can improve the diagnostic ability of AFP for HBV-associated HCC. Hypermethylation of genes in animals will silence genes, resulting in lower gene expression (30)(31)(32), while hypomethylation will reduce gene silencing and increase gene expression (33,34). So we guessed that the hypomethylation of IL-6 increased the expression of IL-6.…”

Alternative Splicing, Epigenetic Modifications and Cancer: A Dangerous Triangle, or a Hopeful One?

“…The combined influence of histone modifications and DNA methylation may result in the selection of cryptic promoters. Apart from the cases discussed by Zardo et al [72], it may be mentioned that of the human DAPK1 gene. Due to its behavior in colorectal cancer [75] and in clear cell renal carcinoma [76], it is considered as a potential tumor suppressor.…”

“…For instance, H3K4me3 inhibits the DNMTs and, consequently, its presence may induce local changes in CpG islands methylation. The aberrant DNA methylation pattern induced by H3K4me3 in cancers has been recently reviewed [72]. Since the early work of Enroth et al [73], many efforts have been made to find a "splicing code", linking specific histone modifications with AS events.…”