Neuroepigenetics
Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.
Mechanisms
Neuroepigenetic mechanisms regulate gene expression in the neuron. Often, these changes take place due to recurring stimuli. Neuroepigenetic mechanisms involve proteins or protein pathways that regulate gene expression by adding, editing or reading epigenetic marks such as methylation or acetylation. Some of these mechanisms include ATP-dependent chromatin remodeling, LINE1, and prion protein-based modifications. Other silencing mechanisms include the recruitment of specialized proteins that methylate DNA such that the core promoter element is inaccessible to transcription factors and RNA polymerase. As a result, transcription is no longer possible. One such protein pathway is the REST co-repressor complex pathway. There are also several non-coding RNAs that regulate neural function at the epigenetic level. These mechanisms, along with neural histone methylation, affect arrangement of synapses, neuroplasticity, and play a key role in learning and memory.Methylation
are involved in regulation of the electrophysiological landscape of the brain through methylation of CpGs. Several studies have shown that inhibition or depletion of DNMT1 activity during neural maturation leads to hypomethylation of the neurons by removing the cell's ability to maintain methylation marks in the chromatin. This gradual loss of methylation marks leads to changes in the expression of crucial developmental genes that may be dosage sensitive, leading to neural degeneration. This was observed in the mature neurons in the dorsal portion of the mouse prosencephalon, where there was significantly greater amounts of neural degeneration and poor neural signaling in the absence of DNMT1. Despite poor survival rates amongst the DNMT1-depleted neurons, some of the cells persisted throughout the lifespan of the organism. The surviving cells reaffirmed that the loss of DNMT1 led to hypomethylation in the neural cell genome. These cells also exhibited poor neural functioning. In fact, a global loss of neural functioning was also observed in these model organisms, with the greatest amounts neural degeneration occurring in the prosencephalon.Other studies showed a trend for DNMT3a and DNMT3b. However, these DNMT's add new methyl marks on unmethylated DNA, unlike DNMT1. Like DNMT1, the loss of DNMT3a and 3b resulted in neuromuscular degeneration two months after birth, as well as poor survival rates amongst the progeny of the mutant cells, even though DNMT3a does not regularly function to maintain methylation marks. This conundrum was addressed by other studies which recorded rare loci in mature neurons where DNMT3a acted as a maintenance DNMT. The Gfap locus, which codes for the formation and regulation of the cytoskeleton of astrocytes, is one such locus where this activity is observed. The gene is regularly methylated to downregulate glioma related cancers. DNMT inhibition leads to decreased methylation and increased synaptic activity. Several studies show that the methylation-related increase or decrease in synaptic activity occurs due to the upregulation or downregulation of receptors at the neurological synapse. Such receptor regulation plays a major role in many important mechanisms, such as the 'fight or flight' response. The glucocorticoid receptor is the most studied of these receptors. During stressful circumstances, there is a signaling cascade that begins from the pituitary gland and terminates due to a negative feedback loop from the adrenal gland. In this loop, the increase in the levels of the stress response hormone results in the increase of GR. Increase in GR results in the decrease of cellular response to the hormone levels. It has been shown that methylation of the I7 exon within the GR locus leads to a lower level of basal GR expression in mice. These mice were more susceptible to high levels of stress as opposed to mice with lower levels of methylation at the I7 exon. Up-regulation or down-regulation of receptors through methylation leads to change in synaptic activity of the neuron.
Hypermethylation, CpG islands, and tumor suppressing genes
are regulatory elements that can influence gene expression by allowing or interfering with transcription initiation or enhancer activity. CGIs are generally interspersed with the promoter regions of the genes they affect and may also affect more than one promoter region. In addition they may also include enhancer elements and be separate from the transcription start site. Hypermethylation at key CGIs can effectively silence expression of tumor suppressing genes and is common in gliomas. Tumor suppressing genes are those which inhibit a cell's progression towards cancer. These genes are commonly associated with important functions which regulate cell-cycle events. For example, PI3K and p53 pathways are affected by CGI promoter hypermethylation, this includes the promoters of the genes CDKN2/p16, RB, PTEN, TP53 and p14ARF. Importantly, glioblastomas are known to have high frequency of methylation at CGIs/promoter sites. For example, Epithelial Membrane Protein 3 is a gene which is involved in cell proliferation as well as cellular interactions. It is also thought to function as a tumor suppressor, and in glioblastomas is shown to be silenced via hypermethylation. Furthermore, introduction of the gene into EMP3-silenced neuroblasts results in reduced colony formation as well as suppressed tumor growth. In contrast, hypermethylation of promoter sites can also inhibit activity of oncogenes and prevent tumorigenesis. Such oncogenic pathways as the transformation growth factor -beta signaling pathway stimulate cells to proliferate. In glioblastomas the overactivity of this pathway is associated with aggressive forms of tumor growth. Hypermethylation of PDGF-B, the TGF-beta target, inhibits uncontrolled proliferation.Hypomethylation and aberrant histone modification
Global reduction in methylation is implicated in tumorigenesis. More specifically, wide spread CpG demethylation, contributing to global hypomethylation, is known to cause genomic instability leading to development of tumors. An important effect of this DNA modification is its transcriptional activation of oncogenes. For example, expression of MAGEA1 enhanced by hypomethylation interferes with p53 function.Aberrant patterns of histone modifications can also take place at specific loci and ultimately manipulate gene activity. In terms of CGI promoter sites, methylation and loss of acetylation occurs frequently at H3K9. Furthermore, H3K9 dimethylation and trimethylation are repressive marks which, along with bivalent differentially methylated domains, are hypothesized to make tumor suppressing genes more susceptible to silencing. Abnormal presence or lack of methylation in glioblastomas are strongly linked to genes which regulate apoptosis, DNA repair, cell proliferation, and tumor suppression. One of the best known examples of genes affected by aberrant methylation that contributes to formation of glioblastomas is MGMT, a gene involved in DNA repair which encodes the protein O6-methylguanine-DNA methyltransferase. Methylation of the MGMT promoter is an important predictor of the effectiveness of alkylating agents to target glioblastomas. Hypermethylation of the MGMT promoter causes transcriptional silencing and is found in several cancer types including glioma, lymphoma, breast cancer, prostate cancer, and retinoblastoma.
Neuroplasticity
refers to the ability of the brain to undergo synaptic rearrangement as a response to recurring stimuli. Neurotrophin proteins play a major role in synaptic rearrangement, amongst other factors. Depletion of neurotrophin BDNF or BDNF signaling is one of the main factors in developing diseases such as Alzheimer's disease, Huntington's disease, and depression. Neuroplasticity can also occur as a consequence of targeted epigenetic modifications such as methylation and acetylation. Exposure to certain recurring stimuli leads to demethylation of particular loci and remethylation in a pattern that leads to a response to that particular stimulus. Like the histone readers, erasers and writers also modify histones by removing and adding modifying marks respectively. An eraser, neuroLSD1, is a modified version of the original Lysine Demethylase 1 that exists only in neurons and assists with neuronal maturation. Although both versions of LSD1 share the same target, their expression patterns are vastly different and neuroLSD1 is a truncated version of LSD1. NeuroLSD1 increases the expression of immediate early genes involved in cell maturation. Recurring stimuli lead to differential expression of neuroLSD1, leading to rearrangement of loci. The eraser is also thought to play a major role in the learning of many complex behaviors and is way through which genes interact with the environment.Neurodegenerative diseases
Alzheimer's disease
is a neurodegenerative disease known to progressively affect memory and incite cognitive degradation. Epigenetic modifications both globally and on specific candidate genes are thought to contribute to the etiology of this disease. Immunohistochemical analysis of post-mortem brain tissues across several studies have revealed global decreases in both 5-methylcytosine and 5-hydroxymethylcytosine in AD patients compared with controls. However, conflicting evidence has shown elevated levels of these epigenetic markers in the same tissues. Furthermore, these modifications appear to be affected early on in tissues associated with the pathophysiology of AD. The presence of 5mC at the promoters of genes is generally associated with gene silencing. 5hmC, which is the oxidized product of 5mC, via , is thought to be associated with activation of gene expression, though the mechanisms underlying this activation are not fully understood.Regardless of variations in results of methylomic analysis across studies, it is known that the presence of 5hmC increases with differentiation and aging of cells in the brain. Furthermore, genes which have a high prevalence of 5hmC are also implicated in the pathology of other age related neurodegenerative diseases, and are key regulators of ion transport, neuronal development, and cell death. For example, over-expression of 5-Lipoxygenase, an enzyme which generates pro-inflammatory mediators from arachidonic acid, in AD brains is associated with high prevalence of 5hmC at the 5-LOX gene promoter region.