Epigenetic Regulation in Human Brain—Focus on Histone Lysine Methylation

Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusettsm USA.
Biological psychiatry (Impact Factor: 10.26). 10/2008; 65(3):198-203. DOI: 10.1016/j.biopsych.2008.08.015
Source: PubMed


Alterations in RNA levels are frequently reported in brain of subjects diagnosed with autism, schizophrenia, depression, and other psychiatric diseases, but it remains unclear whether the underlying molecular pathology involves changes in gene expression, as opposed to alterations in messenger RNA processing. Pre-clinical studies have revealed that stress, drugs, and a variety of other environmental factors lead to changes in RNA levels in brain via epigenetic mechanisms, including modification of histone proteins. A number of site-specific modifications of the nucleosome core histones-including the trimethylated forms of histone H3 lysines K4, K9, and K27-are of particular interest for postmortem research, because these marks differentiate between active and inactive chromatin and seem to remain relatively stable during tissue autolysis. Therefore, histone methylation profiling at promoter regions could provide important clues about mechanisms of gene expression in human brain during development and in disease. Intriguingly, mutations within the genes encoding the H3K9-specific methyltransferase, EHMT1, and the H3K4-specific histone demethylase, JARID1C/SMCX, have been linked to mental retardation and autism, respectively. In addition, the H3K4-specific methyltransferase, MLL1, is essential for hippocampal synaptic plasticity and might be involved in cortical dysfunction of some cases of schizophrenia. Together, these findings emphasize the potential significance of histone lysine methylation for orderly brain development and also as a molecular toolbox to study chromatin function in postmortem tissue.

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Available from: Schahram Akbarian
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    • "In addition to genetic factors, epigenetics is increasingly being investigated for its potential role in integrating environmental exposures and determining disease susceptibility. Epigenetic mechanisms are responsible for heritable changes in gene expression that are not a consequence of changes in the DNA sequence (Bird, 2002, 2007; Weaver et al. 2007; Akbarian & Huang, 2009; Bale et al. 2010; Murgatroyd & Spengler, 2011; Booij et al. 2013). Factors influencing the patterns of epigenetic modification include cell type, developmental stage and the nature and severity of environmental stressors. "
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    ABSTRACT: Background: Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the 'gold standard' for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life. Method: In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored. Results: Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges. Conclusions: The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.
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    • "Methylated lysine residues of histone tails can be mono-, di-, or trimethylated (Lachner and Jenuwein 2002; Martin and Zhang 2005) and, depending on the lysine residue methylated, a differential effect on gene transcription is observed. For example, dimethylation of histone H3 lysine 9 (H3K9me2) promotes gene silencing (Rea et al. 2000; Covington et al. 2011), whereas trimethylation of histone H3 at lysine 4 (H3K4me3) promotes gene transcription (Schneider et al. 2004; Akbarian and Huang 2009). Furthermore, these different histone methylation modifications are regulated by a unique set of histone lysine methyltransferases (H/KMT) and histone lysine demethylases (H/KDM), suggesting a coordinated regulation of histone lysine methylation modifications controls gene transcription in neurons. "
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    ABSTRACT: It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B- but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation.
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    • "Despite the epigenetic neuroscience field ' s youth, the hypothesis that methyltransferases/demethylases play an especially important role in cognition is gaining credi bility. Researchers are rapidly finding neurologic indications associated with dysregulated histone lysine methylation profiles, suggesting that more in-depth knowledge on the topic could bestow therapeutic value (Akbarian and Huang, 2009). As behavioral neuroscientists , we are consistently developing novel pharmaceutical approaches for cognitive enhancement, accelerated re-learning, and improved memory retention with cognitive disorders. "
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    ABSTRACT: Abstract Histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. In this review, we discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory formation and storage. In addition, we address the current literature highlighting the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration. Further, we discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone.
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