The expanding scope and impact of epigenetic cytosine modifications

Abstract

Chemical modifications to genomic DNA can expand and shape its coding potential. Cytosine methylation in particular has well-established roles in regulating gene expression and defining cellular identity. The discovery of TET family enzymes opened a major frontier beyond DNA methylation, revealing three oxidized forms of cytosine that could mediate DNA demethylation or encode independent epigenetic functions. Chemical biology has been instrumental in uncovering TET’s intricate reaction mechanisms and scope of reactivity on a surprising variety of substrates. Moreover, innovative chemoenzymatic strategies have enabled sensitive detection of oxidized cytosine products in vitro and in vivo. We highlight key recent developments that demonstrate how chemical biology is advancing our understanding of the extended, dynamic epigenome.

Transcriptional Addiction in Cancer

“…Methylation of CTCF loop anchor sites prevents CTCF binding and can thus alter insulated neighborhood structure (Ghirlando and Felsenfeld, 2016; Liu et al, 2016b). Cytosine methylation and hydroxymethylation present spatially positioned chemical motifs that can be recognized by chromatin-associated proteins (e.g., meCP2), thereby influencing transcriptional regulation (Baubec et al, 2013; Liu et al, 2016a; Mellen et al, 2012). …”

Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine

“…TET enzymes catalyze the oxidation of 5-methylcytosine (mC), the mainstay of the epigenome, into three additional bases: 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxylcytosine (caC) 1–6 . Mounting evidence suggests that these oxidized mC (ox-mC) bases stably populate mammalian genomes, aid in DNA demethylation, and potentially encode unique epigenetic information 7–11 . The central questions now facing the field involve the functions of each individual base and the mechanisms governing their formation.…”

Chemoselective labeling and site‐specific mapping of 5‐formylcytosine as a cellular nucleic acid modification

“…In mammals, the cytosine methylation pattern is established during embryonic development by de novo DNA methyltransferases DNMT3a and DNMT3b, and maintained during cell division by maintenance DNA methyltransferase DNMT1 [1,3,4,10]. This DNA methylation pattern can be lost through passive or active pathways.…”

“…Methylation at the fifth position of cytosine (C) to give 5-methylcytosine (5mC) at CpG dinucleotide sites constitutes an important epigenetic DNA modification [1][2][3][4][5][6] that is involved in diverse biological processes such as regulation of the transcriptional profile of a cell, mediation of genomic imprinting, X-chromosome inactivation, and repetitive element repression. A fine-tuned balance of ongoing DNA methylation and demethylation is of vital importance for living cells, since dysregulation of these processes results in aberrant 5mC patterns, which contribute to various human diseases, among them neurological disorders such as Alzheimer's or Parkinson's disease [7,8], type 2 diabetes, and, in particular, various types of cancer [1,2,9].…”