Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury

The fetal brain is adapted to the hypoxic conditions present during normal in utero development. Relatively more hypoxic states, either chronic or acute, are pathologic and can lead to significant long-term neurodevelopmental sequelae. In utero hypoxic injury is associated with neonatal mortality and millions of lives lived with varying degrees of disability.

Genetic studies of children with neurodevelopmental disease indicate that epigenetic modifiers regulating DNA methylation and histone remodeling are critical for normal brain development. Epigenetic modifiers are also regulated by environmental stimuli, such as hypoxia. Indeed, epigenetic modifiers that are mutated in children with genetic neurodevelopmental diseases are regulated by hypoxia in a number of preclinical models and may be part of the mechanism for the long-term neurodevelopmental sequelae seem in children with hypoxic brain injury. Thus, a comprehensive understanding the role of DNA methylation and histone modifications in hypoxic injury is critical for developing novel strategies to treat children with hypoxic injury.

This review focuses on our current understanding of the intersection between epigenetics, brain development, and hypoxia. Opportunities for the use of epigenetics as biomarkers of neurodevelopmental disease after hypoxic injury and potential clinical epigenetics targets to improve outcomes after injury are also discussed. While there have been many published studies on the epigenetics of hypoxia, more are needed in the developing brain in order to determine which epigenetic pathways may be most important for mitigating the long-term consequences of hypoxic brain injury.