Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine

Abstract

Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulation and its flexibility. DNA methylation and demethylation is a key mechanism of genome programming and reprogramming. During ontogenesis, the DNA methylome undergoes both programmed changes and those induced by environmental and endogenous factors. The former enable accurate activation of developmental programs; the latter drive epigenetic responses to factors that directly or indirectly affect epigenetic biochemistry leading to alterations in genome regulation and mediating organism response to environmental transformations. Adverse environmental exposure can induce aberrant DNA methylation changes conducive to genetic dysfunction and, eventually, various pathologies. In recent years, evidence was derived that apart from 5-methylcytosine, the DNA methylation/demethylation cycle includes three other oxidative derivatives of cytosine—5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally induced adverse effects on 5hmC patterns in mammalian genomes. Types of environmental exposure under consideration include hypnotic drugs and medicines (i.e., phenobarbital, diethylstilbestrol, cocaine, methamphetamine, ethanol, dimethyl sulfoxide), as well as anthropogenic pollutants (i.e., heavy metals, particulate air pollution, bisphenol A, hydroquinone, and pentachlorophenol metabolites). We put a special focus on the discussion of molecular mechanisms underlying environmentally induced alterations in DNA hydroxymethylation patterns and their impact on genetic dysfunction. We conclude that DNA hydroxymethylation is a sensitive biosensor for many harmful environmental factors each of which specifically targets 5hmC in different organs, cell types, and DNA sequences and induces its changes through a specific metabolic pathway. The associated transcriptional changes suggest that environmentally induced 5hmC alterations play a role in epigenetically mediated genome flexibility. We believe that knowledge accumulated in this review together with further studies will provide a solid basis for new approaches to epigenetic therapy and chemoprevention of environmentally induced epigenetic toxicity involving 5hmC patterns.

Epigenetics of Alzheimer’s Disease

“…5hmC as such serves a dual role, not only as an intermediate of active demethylation, but as an important mark of epigenetic regulation as well. Similarly, as with DNA methylation, numerous environmental factors such as medications and pollutants can affect levels of 5hmC [ 36 ].…”

Ionizing Radiation-Induced Epigenetic Modifications and Their Relevance to Radiation Protection

“…Among the mechanisms leading to global DNA de-methylation/hypomethylation, an important one is the oxidation of 5 mC to 5-hydroxymethylcytosine (5 hmC), which serves as an intermediate in active DNA demethylation [ 118 , 119 ]. In addition, oxidation of guanine to 8-Oxo-2′-deoxyguanosine (8-oxo-dG) can create mismatches via pairing with A, thus leading to G > T transversion.…”

DNA Methylation Dysfunction in Chronic Kidney Disease

“…It is worth highlighting the role of 5-hydroxymethylcytosine (5hmC) [59], a stable cytosine modifier endowed with its own functions in the enzymatic processing of 5-methylcytosine as a part of DNA demethylation system (Figure 4). hypertension, present in the TT genotype population, which in turn represents a major modifiable risk factor for stroke and CVD [57].…”

“…It is worth highlighting the role of 5-hydroxymethylcytosine (5hmC) [59], a stable cytosine modifier endowed with its own functions in the enzymatic processing of 5-methylcytosine as a part of DNA demethylation system (Figure 4). 5hmC is a rather stable product of DNA demethylation, together with 5-formylcytosine, and 5carboxylcytosine, all generated by the catalytic action of the Ten-Eleven-Translocation (TET) family which oxidize methylated cytosines.…”

“…It is worth highlighting the role of 5-hydroxymethylcytosine (5hmC) [ 59 ], a stable cytosine modifier endowed with its own functions in the enzymatic processing of 5-methylcytosine as a part of DNA demethylation system ( Figure 4 ).…”