Epigenetic advances in clinical neuroscience.

Epigenetics, broadly defined as the regulation of gene expression without alteration of the genome, has become a field of tremendous interest in neuroscience, neurology, and psychiatry. This research has rapidly changed the way researchers think about brain function. Exciting epigenetic discoveries have been found in addiction, early life stress, neurodegeneration, post-traumatic stress disorder, and depression. As researchers more precisely define the epigenetic landscape that regulates disease progression in each of these cases, therapeutics can be designed to specifically target the molecules that mediate these epigenetic processes. Further, epigenetics may lead, to the identification of novel biomarkers for diagnosis and for the monitoring of treatment. Epigenetic profiling is likely to become a routine tool for the diagnosis of neurological and psychiatric disorders in the near future.

Although the term “epigenetics” has been used since 1942 to describe the interaction between genes and environment, [1] the last decade has seen a dramatic rise in interest in epigenetic processes in the brain. The term epigenetics is typically used by neuroscientists to describe the long-term regulation of gene expression that may or may not be heritable. Evidence has linked histone modifications, nucleosome repositioning, covalent modification of DNA, and noncoding RNAs to important processes such as neuronal development, synaptic plasticity, and memory. Importantly, the dysregulation of epigenetic processes has been observed in disease states such as neurodegeneration, addiction, depression, and stress. This wide range of disorders with epigenetic components may indicate that epigenetic mechanisms are a broad regulator of neuronal function, and that perturbing the delicate balance of epigenetic marks can cause severe problems in brain function. Research into characterizing and modifying the epigenome promises to yield insight into the mechanisms and future treatment of disorders of the brain. Specifically, major advances are being made through epigenetic research in disease etiology, biomarkers, and novel therapeutics.

Despite tremendous efforts to understand the mechanisms that underlie neurological diseases, many disorders of the brain are still poorly understood. Discoveries of mutations in epigenetic regulators or aberrant epigenetic modifications have begun to explain the molecular processes that may lead to disease states for some of these diseases. For example, a recent genetic study identified a mutation in important residues of histone variant H3.3 that can lead to pediatric glioblastoma in 31% of tumors, directly implicating specific histone residues in disease pathology for the first time.[2] Experiences during early development have also been shown to regulate adult behavior through epigenetic mechanisms. A seminal study from the lab of Michael Meaney demonstrated that maternal care regulates DNA methylation of the glucocorticoid receptor and future response to stress.[3] This effect can be reversed by the application of histone deacetylase (HDAC) inhibitors, which increase the activating histone acetylation mark, indicating a crosstalk between these two modifications. Histone acetylation was also discovered to be regulated by cocaine intake.[4] Studies have since discovered that HDAC inhibitors, which increase histone acetylation, have increased sensitivity to cocaine,[4] while mice with reduced function of CREB-binding protein (CBP), a histone acetyltransferase (HAT), have reduced histone acetylation and sensitivity to cocaine.[5] Other epigenetic mechanisms, such as miRNAs[6] and DNA methylation,[7] have also been shown to regulate cocaine sensitivity, indicating a complex regulation of gene expression that occurs in response to this drug. This research has fostered a new understanding of addiction and potential treatments for those suffering from this problem.

In addition to discovering novel disease mechanisms, studying epigenetics in neurological disease has also led to a number of advances in biomarker identification. There are distinct changes in DNA methylation that occur in response to post-traumatic stress disorder (PTSD) depending on whether or not childhood abuse has also occurred.[8] DNA for this study was extracted from peripheral blood cells of patients with PTSD, indicating that blood may provide an easy readout of epigenetic events in the brain, and ultimately of neurologic function. This finding may allow doctors to develop specialized treatment for individuals that have PTSD with childhood abuse. DNA methylation also appears to play a role in major depressive disorder (MDD). Monozygotic twin studies have identified increased variance in DNA methylation[9] and two reproducible differentially methylated regions[10] in the twin with MDD compared with their unaffected sibling. Additionally, epigenetic biomarkers have been found in the placenta for maternal stress exposure. O-linked N-acetylglucosamine (O-GlcNAc) transferase regulates the function of RNA polymerase II and histone deacetylases, and is expressed at lower levels in the placenta after early prenatal stress. [11] The biomarkers identified in these studies can help provide early intervention and personalized medicine to patients who are likely to struggle with future neurological diseases.

A major promise of epigenetic research in the brain is the ability to discover and target novel pathways that regulate disease progression. This goal has come to fruition in the field of oncology, where two HDAC inhibitors (vorinostat and romidepsin) have already been approved for use in the clinic, and manymore are being investigated in large clinical trials.[12] Drugs targeting epigenetic regulators in the brain have been slower to reach the clinic, but there are FDA-approved epigenetic regulators for disorders of the brain. The HDAC inhibitor valproic acid is approved to treat epilepsy and bipolar mania, but it has multiple other targets and is generally poorly tolerated.[13] More specific targeting of regulators will be necessary to treat specific neurological disorders without affecting total brain function. Advances have come in the field of cognition, where research has indicated that blocking HDAC2[14] and HDAC3[15] enhance long-term memory specifically without affecting short-term memory. These findings have been extended to Alzheimer's disease, an extreme example of memory loss. Studies have found that selectively inhibiting class I HDACs, such as HDAC2 and HDAC3,[16] or selectively inhibiting HDAC6[17] can reverse the memory deficits seen in mouse models of Alzheimer's disease. Although clinical trials have yet to test these drugs in patients suffering from Alzheimer's disease, FDA-approved HDAC inhibitors that reverse the cognitive effects of Alzheimer's disease, like valproic acid,[18] may be the first test.

The past decade has seen an explosion of research into the epigenetic mechanisms regulating neuronal function and dysfunction. Although drugs have not yet reached the clinic based on this research, there are promising breakthroughs occurring in mouse models of disease that are likely to lead to novel therapeutic advances. Epigenetic targets are becoming increasingly important in disease etiology research, biomarker discovery, and novel therapeutics targeting diseases such as addiction, PTSD, depression, and Alzheimer's disease. As epigenetic targets get more carefully defined in these contexts, so too will therapeutic advances. Epigenetics studies in the brain promise to be an exciting field of research that will open up new avenues for treating neurological disease.