Epigenetic regulation of corticotropin-releasing hormone receptor 1: implication for anxiety-related disorders

Abstract

Recent literature corroborates that both, genes and environment, are crucial determinants contributing to psychiatric disorders. The selectively bred mouse models of enhanced fear and anxiety-related behavior provide a unique opportunity to study the interaction of a rigid genetic predisposition with environmental factors and are used to identify targets contributing to pathological anxiety. Here, we studied gene × environment (G×E) interactions using a mouse model of high (HAB) vs. low (LAB) anxiety-related behavior. By applying enriched environment (EE) and chronic mild stress (CMS), we succeeded in shifting the phenotypes of HAB and LAB mice towards “normal” anxiety. In this bidirectional shift, Crhr1 was identified to be a key player. Increased methylation of CpG1 within the Crhr1 promoter region was shown to be critically involved in regulating the binding affinity of the transcription factor Ying-Yang 1 (YY1). The interplay between YY1 expression and DNA methylation might be the mechanism underlying the differences in Crhr1 expression after EE and CMS. Other epigenetic mechanisms contributing to Crhr1 expression are discussed here.