The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD⁺, S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism-sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. Antioxid. Redox Signal. 15, 551–589.

1. Introduction

2. Epigenetic Control of Gene Expression

   1. Histone methylation

      1. Histone methyltransferases

      2. History of histone demethylation

      3. Mechanisms of histone demethylases

      4. Kinetic considerations of histone demethylases

   2. Histone acetylation

      1. Histone acetyltransferases

      2. Histone deacetylases

      3. Nonsirtuin HDACs

      4. Sirtuin deacetylases

   3. Histone ADP-ribosylation

      1. PARP activity and functionality

      2. Indirect effects of ADP-ribosylation

   4. DNA methylation

      1. DNA methyltransferases

      2. DNA demethylases

   5. Noncoding RNA and epigenetic regulation

      1. Long ncRNAs

      2. Short ncRNAs

3. Epigenetic Regulation and Redox Metabolism

4. Redox Metabolism

   1. The citric acid cycle and intermediates of central metabolism

      1. 2-Hydroxyglutarate: oncometabolite or normal regulator?

   2. GSH and the recycling of SAM

   3. The NAD⁺/NADH ratio

      1. The NAD⁺/NADH ratio and central metabolism

      2. Caloric restriction, the NAD⁺/NADH ratio, and sirtuins

      3. PARP, NAD⁺, and sirtuin activity

      4. Plasma membrane redox system and NAD⁺

   4. Maintenance of the intracellular iron redox status and epigenetic enzymes

      1. Labile iron and oxidative stress

      2. Iron–sulfur center proteins and epigenetic modification

      3. Direct interaction with epigenetic enzyme iron loading

      4. Ascorbate and 2-OG and Fe(II)-dependent dioxygenases

      5. Nitric oxide and iron

   5. Redox regulation and noncoding RNA

   6. Direct modulation of HDAC activity by ROS

   7. Oxygen tension and epigenetic phenomena

5. Toward a Global Model for Redox Epigenetic Maintenance

6. Metabolic Epigenetics and Disease

   1. Cardiovascular disease

   2. Alzheimer disease

   3. Cancer

   4. Environmental toxicology and epigenetics

      1. Alcohol

7. Challenges and Future Directions

8. Conclusions