Neuroepigenomics in Aging and Disease

Deussing, Jan M., Jakovcevski, Mira, Jan M. Deussing Ph.D., Mira Jakovcevski Ph.D., Jan M. Deussing, Mira Jakovcevski

Raul Delgado-Morales

Major depressive disorder (MDD) is a multifactorial disease, weakly linked to multiple genetic risk factors. In contrast to that, environmental factors and "gene × environment" interaction between specific risk genes and environmental factors, such as severe or early stress exposure, have been strongly linked to MDD vulnerability. Stressors can act on the interface between an organism and the environment, the epigenome. The molecular foundation for the impact of stressors on the risk to develop MDD is based on the hormonal stress response itself: the glucocorticoid receptor (GR, encoded by NR3C1). NR3C1 can directly interact with the epigenome in the cell nucleus. Besides DNA methylation, histone modifications have been reported to be crucial targets for the interaction with the stress response system. Here, we review critical findings on the impact of the most relevant histone modifications, i.e. histone acetylation and methylation, in the context of MDD and related animal models. We discuss new treatment options which have been based on these findings, including histone deacetylase inhibitors (HDACis) and drugs targeting specific histone marks, closely linked to psychiatric disease. In this context we talk about contemporary and future approaches required to fully understand (1) the epigenetics of stress-related disease and (2) the mode of action of potential MDD drugs targeting histone modifications. This includes harnessing the unprecedented potentials of genome-wide analysis of the epigenome and transcriptome, in a cell type-specific manner, and the use of epigenome editing technologies to clearly link epigenetic marks on specific genomic loci to functional relevance.