Neuroscience
-
A large, and still rapidly expanding literature on epigenetic regulation in the nervous system has provided fundamental insights into the dynamic regulation of DNA methylation and post-translational histone modifications in the context of neuronal plasticity in health and disease. Remarkably, however, very little is known about the potential role of chromatin-bound RNAs, including many long non-coding transcripts and various types of small RNAs. ⋯ Examples of recently discovered chromatin-bound long non-coding RNAs important for neuronal health and function include the brain-derived neurotrophic factor antisense transcript (Bdnf-AS) which regulates expression of the corresponding sense transcript, and LOC389023 which is associated with human-specific histone methylation signatures at the chromosome 2q14.1 neurodevelopmental risk locus by regulating expression of DPP10, an auxillary subunit for voltage-gated K(+) channels. We predict that the exploration of chromatin-bound RNA will significantly advance our current knowledge base in neuroepigenetics and biological psychiatry.
-
During all stages of neural development-from the fate switches of neural precursor/progenitor cells to activity-dependent synapse maturation-chromatin-level modifications are important regulators of the gene expression that control developmental programs. Such modifications, including both alterations of histone tails and cytosine residues in the DNA, as well as changes in the chromatin structure, act dynamically throughout development and work together to determine the chromatin state at each time point. While many studies have shown localized action of chromatin modifiers at relevant gene loci, recent reports have also indicated that some chromatin modifications work on a more global scale, altering many loci throughout the genome. Here we review recent papers that describe the roles of chromatin-level regulation, at both the local and global scale, in the development of the mouse brain.
-
The nervous system of higher organisms is characterized by an enormous diversity of cell types that function in concert to carry out a myriad of neuronal functions. Differences in connectivity, and subsequent physiology of the connected neurons, are a result of differences in transcriptional programs. The extraordinary complexity of the nervous system requires an equally complex regulatory system. ⋯ However, an additional level of regulation is provided by epigenetic controls. Among various epigenetic processes, nuclear organization and the control of genome architecture emerge as an efficient and powerful form of gene regulation that meets the unique needs of the post-mitotic neuron. Here, we present an outline of how nuclear architecture affects transcription and provide examples from the recent literature where these principles are used by the nervous system.
-
Genetic factors are implicated in the heritability of drug abuse. However, even with advances in current technology no specific genes have been identified that are critical for the transmission of drug-induced phenotypes to subsequent generations. ⋯ Therefore, the epigenome provides a direct mechanism for drugs of abuse to influence the genetic events involved in the development of addiction as well as its heritability to subsequent generations. In this review we discuss the mechanisms underlying intergenerational epigenetic transmission, highlight studies that demonstrate this phenomenon with particular attention to the field of addiction, and identify gaps for future studies.
-
Developing novel therapeutics and diagnostic tools based upon an understanding of neuroplasticity is critical in order to improve the treatment and ultimately the prevention of a broad range of nervous system disorders. In the case of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), where diagnoses are based solely on nosology rather than pathophysiology, there exists a clear unmet medical need to advance our understanding of the underlying molecular mechanisms and to develop fundamentally new mechanism experimental medicines with improved efficacy. In this context, recent preclinical molecular, cellular, and behavioral findings have begun to reveal the importance of epigenetic mechanisms that alter chromatin structure and dynamically regulate patterns of gene expression that may play a critical role in the pathophysiology of mood disorders. ⋯ Looking beyond current knowledge, we discuss how high-resolution, whole-genome methodologies, such as RNA-sequencing (RNA-Seq) for transcriptome analysis and chromatin immunoprecipitation-sequencing (ChIP-Seq) for analyzing genome-wide occupancy of chromatin-associated factors, are beginning to provide an unprecedented view of both specific genomic loci as well as global properties of chromatin in the nervous system. These methodologies when applied to the characterization of model systems, including those of patient-derived induced pluripotent cell (iPSC) and induced neurons (iNs), will greatly shape our understanding of epigenetic mechanisms and the impact of genetic variation on the regulatory regions of the human genome that can affect neuroplasticity. Finally, we point out critical unanswered questions and areas where additional data are needed in order to better understand the potential to target mechanisms of chromatin-mediated neuroplasticity for novel treatments of mood and other psychiatric disorders.