Epigenetic Modifications of Cytosine: Biophysical Properties, Regulation, and Function in Mammalian DNA

Abstract

To decode the function and molecular recognition of several recently discovered cytosine derivatives in the human genome - 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine - a detailed understanding of their effects on the structural, chemical, and biophysical properties of DNA is essential. Here, we review recent literature in this area, with particular emphasis on features that have been proposed to enable the specific recognition of modified cytosine bases by DNA-binding proteins. These include electronic factors, modulation of base-pair stability, flexibility, and radical changes in duplex conformation. We explore these proposals and assess whether or not they are supported by current biophysical data. This analysis is focused primarily on the properties of epigenetically modified DNA itself, which provides a basis for discussion of the mechanisms of recognition by different proteins.

Defining the impact of sumoylation on substrate binding and catalysis by thymine DNA glycosylase

“…Thus, TDG has high specificity for G·fC and G·caC pairs, binding these sites with ΔΔG bind of 2.5 kcal/mol and 2.9 kcal/mol, respectively, compared to nonspecific DNA (or ΔΔG bind of 1.6 kcal/mol and 2.0 kcal/mol relative to an unmodified CpG site). Because fC and caC impart only small, localized changes to DNA structure ( 64 , 65 ), the specificity of TDG for these sites is likely explained largely by specific interactions that it forms with the formyl and carboxyl groups, as observed in crystal structures ( 50 , 51 ). Although the affinity of TDG for G·hmC pairs has not been reported, evidence that TDG does not form specific interactions with the hydroxyl of hmC is provided by findings that the TDG catalytic domain (residues 111–308; TDG 111–308 ) lacks detectable affinity for G·hmC (or G·mC) pairs while it binds specifically to G·fC ( K d 130 nM) and G·caC ( K d 70 nM) pairs ( 50 ).…”

Intensive gestational glycemic management and childhood obesity: a systematic review and meta-analysis

“…exposures and interventions throughout life will counteract or amplify this risk in an incremental manner. In fact, there is preliminary evidence of the active reversibility of DNA methylation through various pathways not involving demethylases and which supports ongoing, active adaptation to environmental cues throughout life (reviewed in 51,52 ). If proven to have physiological relevance, the active reversibility of DNA methylation would disrupt the currently accepted view that DNA methylation is mostly irreversible and potentially force a revision of the "critical windows" concept.…”

Epigenetic control of the angiotensin-converting enzyme in endothelial cells during inflammation

“…CpG islands are CG-rich regions with a CG content over 50% and an expected to observed CG ratio over 60%, covering a distance of at least 200 bp [27,28], and are often enriched at promoter sites and 5’-untranslated regions [26,29]. In general, promoter hypermethylation results in condensed chromatin structures and hence reduced transcription rates [30], largely due to hindered transcription factor binding. In this study the transcription factor MAX was the main focus as the ACE promoter region contains a CpG island that harbors two MAX binding sites.…”