Clinical Implications of Epigenetic Dysregulation in Perinatal Hypoxic-Ischemic Brain Damage

Abstract

Placental and fetal hypoxia caused by perinatal hypoxic-ischemic events are major causes of stillbirth, neonatal morbidity, and long-term neurological sequelae among surviving neonates. Brain hypoxia and associated pathological processes such as excitotoxicity, apoptosis, necrosis, and inflammation, are associated with lasting disruptions in epigenetic control of gene expression contributing to neurological dysfunction. Recent studies have pointed to DNA (de)methylation, histone modifications, and non-coding RNAs as crucial components of hypoxic-ischemic encephalopathy (HIE). The understanding of epigenetic dysregulation in HIE is essential in the development of new clinical interventions for perinatal HIE. Here, we summarize our current understanding of epigenetic mechanisms underlying the molecular pathology of HI brain damage and its clinical implications in terms of new diagnostic, prognostic, and therapeutic tools.

Keywords: DNA methylation; biomarker; histone modifications; hypoxia; hypoxic-ischemic encephalopathy; ischemia; microRNAs.

Figure 1

Different risk factors, which can be ante-, peri-, or postnatal can lead to perinatal hypoxia. If prolonged hypoxia results in a perturbed brain environment, leading to modulated epigenetic changes that alter the gene expression profile as an adaption of the fetus to the adverse environment. Different epigenetic mechanisms cooperatively orchestrate this process. As a result, changes in physiology of the neonatal brain can permanently affect the structure and/or functionality, and result in increased disease susceptibility in the offspring. EAAs, excitatory amino acids; miRNA, microRNA; ciRNA, circular RNA; lncRNA, long non-coding RNA.