Epigenetic Regulation in Neurodegenerative Diseases

Genome-wide studies have begun to characterize epigenetic changes in neurodegenerative diseases. Both global and local alterations in the levels of multiple histone marks have been identified. The impact of these alterations on gene expression is not clear in all situations, and other mechanisms likely contribute to transcriptional dysregulation in the degenerative brain. Loss of chromatin dynamics occurs in aging and neurodegenerative diseases. However, these are separate states and the chromatin landscape of the neurodegenerative brain is distinct from that of the healthy aged brain. Advances in brain chromatin technology now include single-cell analysis of DNA methylation and histone modifications. In multiple animal models of neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, reversing aberrant chromatin structure mitigates toxicity of disease-associated proteins. Epigenetic editing may prove a useful tool to alter locus-specific chromatin structure and avoid non-histone targets of small molecule inhibitors. Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches. Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.