Role of Epigenetic Changes in Radiation-Induced Genome Instability

摘要

Ionizing radiation (IR) is an important diagnostic and treatment modality, yet it is also a potent genotoxic agent that causes genome instability and carcinogenesis. While modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem as radiation poses a threat to the exposed individuals and their progeny. Radiation-induced genome instability, which manifests as an elevated mutation rate (both delayed and non-targeted), chromosomal aberrations and changes in gene expression, has been well-documented in directly exposed cells and organisms. However, it has also been observed in distant, naive, out-of-field, 'bystander' cells and their progeny. Enigmatically, this increased instability is even observed in the pre-conceptually exposed progeny of animals, including humans. The mechanisms by which these distal effects arise remain obscure and, recently, have been proposed to be epigenetic in nature. Epigenetic alterations which comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in health and disease. Three major areas of epigenetics-DNA methylation, histone modifications and small RNA-mediated silencing, are known to have profound effects on controlling gene expression. Yet, the exact nature of the epigenetic changes and their precise roles in IR responses and IR-induced genome instability still need to be delineated. Here we will focus on the nature of epigenetic changes in directly exposed and bystander tissues. We will also discuss the emerging evidence that support the role of epigenetic deregulation in transgenerational effects.