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Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell (motor, sensory, or both) affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.
Neurodengenerative diseases of motor neurons can cause degeneration of motor neurons involved in voluntary muscle control such as muscle contraction and relaxation. This article will cover the epigenetics and treatment of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). See the Motor Neuron Fact Sheet [1] for details regarding other motor neuron diseases. Neurodegenerative diseases of the central nervous system can affect the brain and spinal cord. This article will cover the epigenetics and treatment of Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). These diseases are characterized by chronic and progressive neuronal dysfunction, sometimes leading to behavioral abnormalities (as with PD), and, ultimately, neuronal death, resulting in dementia.
Neurodegenerative diseases of sensory neurons can cause degeneration of sensory neurons involved in transmitting sensory information such as hearing and seeing. The main group of sensory neuron diseases are hereditary sensory and autonomic neuropathies (HSAN) such as HSAN I, HSAN II, and Charcot-Marie-Tooth Type 2B (CMT2B). [2] [3] Though some sensory neuron diseases are recognized as neurodegenerative, epigenetic factors have not yet been clarified in the molecular pathology.
The term epigenetics refers to three levels of gene regulation: (1) DNA methylation, (2) histone modifications, and (3) non-coding RNA (ncRNA) function. Briefly, histone-mediated transcriptional control occurs by the wrapping of DNA around a histone core. This DNA-histone structure is called a nucleosome; the more tightly the DNA is bound by the nucleosome, and the more tightly a string of nucleosomes are compressed among each other, the greater the repressive effect on transcription of genes in the DNA sequences near or wrapped around the histones, and vice versa (i.e. looser DNA binding and relaxed compaction leads to a comparatively derepressed state, resulting in facultative heterochromatin or, even further derepressed, euchromatin). At its most repressive state, involving many folds into itself and other scaffolding proteins, DNA-histone structures form constitutive heterochromatin. This chromatin structure is mediated by these three levels of gene regulation. The most relevant epigenetic modifications to treatment of neurodegenerative diseases are DNA methylation and histone protein modifications via methylation or acetylation. [4] [5]
Epigenetic drugs target the proteins responsible for modifications on DNA or histone. Current epigenetic drugs include but are not limited to: HDAC inhibitors (HDACi), HAT modulators, DNA methyltransferase inhibitors, and histone demethylase inhibitors. [7] [8] The majority of epigenetic drugs tested for use against neurodegenerative diseases are HDAC inhibitors; however, some DNMT inhibitors have been tested as well. While the majority of epigenetic drug treatments have been conducted in mouse models, some experiments have been performed on human cells as well as in human drug trials (see table below). There are inherent risks in using epigenetic drugs as therapies for neurodegenerative disorders as some epigenetic drugs (e.g. HDACis such as sodium butyrate) are non-specific in their targets, which leaves potential for off-target epigenetic marks causing unwanted epigenetic modifications.
Function | Classification | Drug | ALS | AD | HD | PD | SMA |
---|---|---|---|---|---|---|---|
DNA-methylation inhibitor | chemical analogue of cytidine | Azathioprine | M (ny) | M (ny) | |||
HDAC inhibitor (small molecule) | benzamide | M344 | MC 19 | ||||
fatty acid | Sodium butyrate | M (y) 5, 6, 7 ; H (ny) | D (y) 11 | M (y) 14; R (y) 15; D (y) 16, 18; H (ny) | MC 20; M (y) 21; H (ny) | ||
Sodium phenylbutyrate | M (y) 1; H (y) 2 | M (y) 8; H (ny) | H (ys) 12 | MC 20; H (v) 21, 22 | |||
Valproic acid | M (y) 2; H (ni) 3 | M (y) 9; H (ny) | D (y) 11 | R (y) 17; H (ny) | MC 23, 24; M (y) 25; H (v) 26, 27, 28, 29 | ||
hydroxamic acid | Trichostatin A | M (y) 4; H (ny) | M (y) 10; H (ny) | MC 13; D (y) 11 | M (y) 30, 31; H (ny) | ||
Vorinostat (suberanilohydroxamic acid-SAHA) | M (y) 9; H (ny) | MC 13; D (y) 11 | D (y) 18 | MC 32, 33; M (y) 34; H (ny) |
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a motor neuron disease that involves neurogeneration. All skeletal muscles in the body are controlled by motor neurons that communicate signals from the brain to the muscle through a neuromuscular junction. When the motor neurons degenerate, the muscles no longer receive signals from the brain and begin to waste away. ALS is characterized by stiff muscles, muscle twitching, and progressive muscle weakness from muscle wasting. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first, usually the limbs. As the disease progresses most patients are unable to walk or use their arms and eventually develop difficulty speaking, swallowing and breathing. Most patients retain cognitive function and sensory neurons are generally unaffected. Patients are often diagnosed after the age of 40 and the median survival time from onset to death is around 3–4 years. In the final stages, patients can lose voluntary control of eye muscles and often die of respiratory failure or pneumonia as a result of degeneration of the motor neurons and muscles required for breathing. Currently there is no cure for ALS, only treatments that may prolong life.
To date, multiple genes and proteins have been implicated in ALS. One of the common themes between many of these genes and their causative mutations is the presence of protein aggregates in motor neurons. [43] Other common molecular features in ALS patients are altered RNA metabolism [44] and general histone hypoacetylation. [45]
ALS patients and mouse models show general histone hypoacetylation that can ultimately trigger apoptosis of cells. [54] In experiments with mice, HDAC inhibitors counteract this hypoacetylation, reactivate aberrantly down-regulated genes, and counteract apoptosis initiation. [13] [55] Furthermore, HDAC inhibitors are known to prevent SOD1 protein aggregates in vitro. [56]
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the SMN1 gene. [59] Symptoms vary greatly with each subset of SMA and the stage of the disease. General symptoms include overall muscle weakness and poor muscle tone including extremities and respiratory muscles leading to difficulty walking, breathing, and feeding. Depending on the type of SMA, the disease can present itself from infancy through adulthood. As SMN protein generally promotes the survival of motor neurons, mutations in SMN1 results in slow degeneration motor neurons leading to progressive system-wide muscle wasting. Specifically, over time, decreased levels of SMN protein results in gradual death of the alpha motor neurons in the anterior horn of the spinal cord and brain. Muscles depend on connections to motor neurons and the central nervous system to stimulate muscle maintenance and therefore degeneration of motor neurons and subsequent denervation of muscles lead to loss of muscle control and muscle atrophy. The muscles of the lower extremities are often affected first followed by upper extremities and sometimes the muscles of respiration and mastication. In general, proximal muscle is always affected more than distal muscle.
Spinal muscular atrophy is linked to genetic mutations in the SMN1 (Survival of Motor Neuron 1) gene. The SMN protein is widely expressed in neurons and serves many functions within neurons including spliceosome construction, mRNA axon transport, neurite outgrowth during development, and neuromuscular junction formation. The causal function loss in SMA is currently unknown.
SMN1 is located in a telomeric region of human chromosome 5 and also contains SMN2 in a centromeric region. SMN1 and SMN2 are nearly identical except for a single nucleotide change in SMN2 resulting in an alternative splicing site where intron 6 meets exon 8. This single base pair change leads to only 10–20% of SMN2 transcripts resulting in fully functional SMN protein and 80–90% of transcripts leading to a truncated protein that is rapidly degraded. Most SMA patients have 2 or more copies of the SMN2 gene with more copies resulting in a decrease in disease severity. [60] Most SMA patients have either point mutations or a deletion in exon 7 often leading to a protein product similar to the truncated and degraded version of the SMN2 protein. In SMA patients this small amount of functional SMN2 protein product allows for some neurons to survive.
Although SMA is not caused by an epigenetic mechanism, therapeutic drugs that target epigenetic marks may provide SMA patients with some relief, halting or even reversing the progression of the disease. As SMA patients with higher copy numbers of the SMN2 gene have less severe symptoms, researchers predicted that epigenetic drugs that increased SMN2 mRNA expression would increase the amount of functional SMN protein in neurons leading to a reduction in SMA symptoms. Histone deacetylase (HDAC) inhibitors are the main compounds that have been tested to increase SMN2 mRNA expression. Inhibiting HDACs would allow for hyperacetylation of the SMN2 gene loci theoretically resulting in an increase in SMN2 expression. [41] Many of these HDAC inhibitors (HDACi) are first tested in mouse models of SMA created through a variety of mutations in the mouse SMN1 gene. If the mice show improvement and the drug does not cause very many side effects or toxicity, the drug may be used in human clinical trials. Human trials with all of the below HDAC inhibitors are extremely variable and often impacted by the patient's exact SMA subtype.
Myasthenia gravis is an autoimmune disease affecting synapses at the neuromuscular junction, whereby antibodies produced primarily in the thymus gland by B-cells associate with postsynaptic nicotinic acetylcholine receptors (AChR), along with other NMJ post-synaptic receptors (MuSK-R and low-density lipoprotein receptor). These antibodies include acetylcholine receptor antibodies, MuSK antibodies, and low-density lipoprotein receptor related protein 4 antibodies (LRP4-Ab). [62] Antibody binding to their respective receptors causes the destruction of those receptors, leading to a reduction in the number of postsynaptic acetylcholinergic receptors and a reduction in overall acetylcholine transport. Disease symptoms include muscular weakness that fatigues due to overuse, but improves with rest. Hallmark symptoms due to muscular weakness include ptosis, double vision, dysphagia, as well as aberrant speech. [63]
Myasthenia gravis is a relatively rare disease, occurring in about 3–30 individuals per 100,000, but has been rising over the past couple decades. There exists two variations of myasthenia gravis with respect to age and gender demographics: early-onset myasthenia gravis, which has a higher incidence among females, and late-onset myasthenia gravis, which has a higher incidence among males. [63]
There has been extensive research on the genetic basis of myasthenia gravis, however evidence does not suggest that it is an inherited disease. [64] There has also been extensive research on the epigenetic contribution to myasthenia gravis. [65] DNA methylation and noncoding RNA, such as miRNA (micro RNA) and long noncoding RNA (lncRNA), are epigenetic factors that play a significant role in increasing the likelihood of acquiring myasthenia gravis. In addition, the thymus is a key organ in the immune response that is often negatively affected by abnormal miRNA expression and DNA methylation.
Micro RNA (miRNA) are single-stranded non-coding RNAs that bind their target mRNAs. From there, they can regulate gene expression by inhibiting translation or degrading the mRNA strand, oftentimes in B-cells and T-cells of the immunological process. With respect to myasthenia gravis, abnormal miRNA function is associated with immunoregulatory pathogenesis, and each miRNA has its own unique downstream effects.
The thymus is an important endocrine organ implicated in myasthenia gravis. In normal, healthy development, the thymus shrinks in size over time. In those with thymus-associated myasthenia gravis there are correlations with thymomas in late-onset myasthenia gravis as well as thymic hyperplasia with germinal centers in early-onset myasthenia gravis, and each of these conditions can be attributed partly to irregular miRNA function. [66] In late-onset myasthenia gravis subjects, it was shown that miRNA-12a-5p expression was increased in thymoma-associated myasthenia gravis. MiRNA-12a-5p inhibits expression of the gene FoxP3, a gene known to be associated with normal thymus development and whose alteration is attributed to thymomas. [67] Additionally, an association between thymoma-associated myasthenia gravis and decreased miR-376a/miR-376c expression was found. Autoimmune regulation is known to be downregulated in thymoma-associated myasthenia gravis, and in thymus cells with downregulated autoimmune regulation there was simultaneous downregulation in miR-376a, miR-376c, and miRNA-12a-5p expression. [67] In early-onset myasthenia gravis patients, 61 miRNA's were found to be either significantly downregulated or upregulated. The most downregulated miRNA was found to be miR-7-5p, whose target gene is CCL21. CCL21 is known to aberrantly recruit B-cells in the thymus of early-onset myasthenia gravis patients, and was found to be highly expressed in early-onset myasthenia gravis patients, potentially explaining the abnormally large amounts of B cells found in thymic hyperplasia. [68]
Aside from miRNA's corresponding to altered thymus function, there are other several key miRNA's that are correlated with myasthenia gravis. MiR-15 cluster (miR-15a, miR-15b, and miR-15c) was shown to be associated with autoimmunity, in that its downregulation increased CXCL10 expression, a target gene involved in T-cell signaling. CXCL10 expression was also shown to be increased in the thymus of myasthenia gravis patients. [69] Additionally, miR-146 was found to be upregulated in myasthenia gravis patients. In these patients with upregulated miR-146, there was a concurrent increase in proteins that correspond to a wide array of immune responses, specifically TLR4, CD40, and CD80. [70]
DNA methylation is the epigenetic process by which methyl groups are added to either adenine or cytosine bases, which results in the repression of that sequence when cytosine methylation occurs. [71] DNA methylation was found to be a factor in increasing the likelihood of acquiring myasthenia gravis, albeit this topic has not been widely researched. Research in China has identified the gene CTLA-4 (cytotoxic T lymphocyte antigen-4) as being highly methylated in myasthenia gravis patients compared to control groups throughout the entire span of the disease. The CTLA-4 gene produces an antigen of the same name that is presented on killer T-cells and allows for the suppression of the immune response. Methylation of this gene represses production of the antigen CTLA-4—a pattern seen in a significant majority of myasthenia gravis patients—and can explain the elevated immune response seen in myasthenia gravis. [72] Furthermore, myasthenia gravis patients with thymic abnormalities (approximately 10–20% of all myasthenia gravis patients) [73] had even higher levels of CTLA-4 methylation than other myasthenia gravis patients. It is not extensively researched why certain genes are hypermethylated in these cases, but information on myasthenia gravis largely points to upregulation of the DNA methyltransferase genes DNMT1, DNMT3A, and DNMT3B in patients with myasthenia gravis. [74]
In addition to CTLA-4 methylation, hypermethylation of the growth hormone secretagogue receptor gene was seen in patients with thymoma-associated late-onset myasthenia gravis. [75] Growth hormone secretagogue receptor hypermethylation is detected in a wide variety of cancers, however only recently has been correlated with the development of thymoma-associated myasthenia gravis. Although it is seen in approximately 1/4 of thymoma-associated myasthenia gravis subjects, it is not a reliable biomarker for the disease, and its relevance to disease progression is not well known.
Long ncRNA (lncRNA) are a second type of non-coding RNA that are key post-transcriptional modifiers of protein-coding gene expression. These also play a significant role in myasthenia gravis. Their aberrant regulation can cause differential expression in downstream genes. For instance, the differential expression of lncRNA interferon gamma antisense RNA negatively regulates the expression of HLA-DRB and HLA-DOB, [75] two genes implicated in the body's autoimmune response by differentiating endogenous and foreign proteins. [76] As seen in myasthenia gravis patients with downregulated lethal (let)-7 lncRNA, it was also found that the level of let-7 lncRNA was negatively correlated with levels of interleukin (IL)-10, a gene responsible for inhibiting cytokine secretion/activation, antigen presentation, and macrophage activity, [77] but also for exhibiting anti-tumor effects. [78] Therefore, the negative correlation between let-7 lncRNA and IL-10 levels and its specific effects on myasthenia gravis development are ambiguous.
In addition to aberrant regulation of downstream target genes, lncRNA also affect expression by acting as competing endogenous RNA (ceRNA). The competing endogenous RNA theory states that transcripts sharing common miRNA binding sites can compete to bind these identical miRNAs, and in this way lncRNAs can bind miRNAs, regulating their downstream binding activity and affecting their function. In the case of myasthenia gravis, the lncRNA small nucleolar RNA host gene (SNHG) 16 regulates the expression of IL-10 by adsorbing let-7c-5p, a miRNA that commonly associates with IL-10, as a competing endogenous RNA.
Diagnosis of myasthenia gravis, individual prognosis, and the level of treatment needed can be determined by detecting the amounts of circulating miRNA.
Immunosuppressants represent a large category in clinical studies for myasthenia gravis treatment, as they reduce the hyperactive immunological response in T-cells presenting acetylcholine receptor-binding antigens. [66] By overexpressing miR-146, studies show that patients with early-onset myasthenia gravis can have antigen-specific suppressive effects. This has implications in reducing the immune response of myasthenia gravis patients and improving prognosis. Likewise, miR-155 is proven to be correlated with myasthenia gravis-associated thymic inflammation and immune response. Research is being conducted whereas repression of miR-155 could reduce these aberrant effects. [66] Lastly, the miRNA's miR-150-5p and miR-21-5p are consistently shown to be elevated in myasthenia gravis patients with acetylcholinergic receptor antibodies (in contrast to the MuSK-binding variant of myasthenia gravis), therefore these two miRNA's are reliable biomarkers in detecting this variant of myasthenia gravis. [79]
Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. The disease is characterized behaviorally by chronic and progressive decline in cognitive function, beginning with short-term memory loss, and neurologically by buildup of misfolded tau protein and associated neurofibrillary tangles, and by amyloid-beta senile plaques amyloid-beta senile plaques. Several genetic factors have been identified as contributing to AD, including mutations to the amyloid precursor protein (APP) and presenilins 1 and 2 genes, and familial inheritance of apolipoprotein E allele epsilon 4. In addition to these common factors, there are a number of other genes that have shown altered expression in Alzheimer's disease, some of which are associated with epigenetic factors.
Treatment for prevention or management of Alzheimer's disease has proven troublesome since the disease is chronic and progressive, and many epigenetic drugs act globally and not in a gene-specific manner. As with other potential treatments to prevent or ameliorate symptoms of AD, these therapies do not work to cure, but only ameliorate symptoms of the disease temporarily, underscoring the chronic, progressive nature of AD, and the variability of methylation in AD brains.
Huntington's disease (HD) is an inherited disorder that causes progressive degeneration of neurons within the cerebral cortex and striatum of the brain [98] resulting in loss of motor functions (involuntary muscle contractions), decline in cognitive ability (eventually resulting in dementia), and changes in behavior. [7]
Huntington's is caused by an autosomal dominant mutation expanding the number of glutamine codon repeats (CAG) within the Huntingtin gene (Htt). [98] The Htt gene encodes for the huntingtin protein which plays a role in normal development but its exact function remains unknown. [99] The length of this CAG repeat correlates with the age-of-onset of the disease. The average person without Huntington's has less than 36 CAG repeats present within the Htt gene. When this repeat length exceeds 36, the onset of neuronal degradation and the physical symptoms of Huntington's can range from as early as 5 years of age (CAG repeat > 70) to as late as 80 years of age (CAG repeat < 39). [100]
This CAG expansion results in mRNA downregulation of specific genes, decreased histone acetylation, and increased histone methylation. [101] [102] The exact mechanism of how this repeat causes gene dysregulation is unknown, but epigenome modification may play a role. For early-onset Huntington's (ages 5–15), both transgenic mice and mouse striatal cell lines show brain specific histone H3 hypoacetylation and decreased histone association at specific downregulated genes within the striatum (namely Bdnf, Cnr1, Drd2 – dopamine 2 receptor, and Penk1 – preproenkephalin). [103] For both late- and early-onset Huntington's, the H3 and H4 core histones associated with these downregulated genes in Htt mutants have hypoacetylation (decreased acetylation) compared to wild-type Htt. [102] [103] This hypoacetylation is sufficient to cause tighter chromatin packing and mRNA downregulation. [102]
Along with H3 hypoacetylation, both human patients and mice with the mutant Htt have increased levels of histone H3 lysine 9 trimethylation. [101] This increase in H3-K9 trimethylation is linked to an increased expression of the methyltransferase ESET/SETDB1 (ERG-associated protein with SET domain (ESET)), which targets and trimethylates H3-K9 residues. [101] It is proposed that this hypermethylation may account for the onset of specific gene repression in Htt mutants. [101]
Huntington patients and both mouse and Drosophila models show histone H3 and H4 hypoacetylation. There are currently no treatments for the disease but numerous HDAC inhibitors have been tested and shown to reverse the certain symptoms caused by the Htt mutation.
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra by causes unknown. Several genes and environmental factors (e.g. pesticide exposure) may play a role in onset of PD. Hallmarks include mutations to the alpha-synuclein gene, SNCA, as well as PARK2, PINK1, UCHL1, DJ1, and LRRK2 genes, and fibrillar accumulation of Lewy bodies from misfolded alpha-synuclein. Symptoms are most noticeably manifested in disorders of movement, including shaking, rigidity, deficits in making controlled movements, and slow and difficult walking. The late stages of the disease result in dementia and depression. Levodopa and dopaminergic therapy may ameliorate symptoms, though there is no treatment to halt progression of the disease.
Epigenetic treatments tested in models of PD are few, though some promising research has been conducted. Most treatments investigated thus far are directed at histone modifications and analysis of their roles in mediating alpha-synuclein expression and activity. Pesticides and paraquat increase histone acetylation, producing neurotoxic effects similar to those seen in PD, such as apoptosis of dopaminergic cells. [115] Despite this, treatment with HDACis [116] seems to have a neuroprotective effect.
Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that does not have a confirmed cause, but is widely considered to be an autoimmune disease in nature. [117] It is indicated by demyelination of the nerves of the brain and spinal cord. Its symptoms are unique in nature and vary, but include those that have degenerative effects in the eyes and limbs. These can present themselves as numbness or atrophy, shock like sensations, paralysis, as well as lack of coordination or tremors, within the extremities. Within the eye, multiple sclerosis can cause blurriness, double vision, pain, or vision loss. Multiple sclerosis effects can be presented throughout other realms of the body, but is largely characterized by these main symptoms. Some of these can include loss of sexual or excretory function and epilepsy. While there are a few subcategories of multiple sclerosis, in most instances, the disease afflicts in a relapsing nature, where relapses of symptoms might not occur for extended periods of time, yielding more to the uncertainty of the disease. There is no known cure for MS, but measures can be taken post relapse to regain loss of function and the symptoms can be mitigated via therapeutic or medicinal means. [118]
Because of the outside factors that precede multiple sclerosis and the heritability typically occurring within the mother, it is thought to have an epigenetic cause. Some factors that may increase the incidence of MS are smoking, vitamin deficiency, and a history of some viral infections—which are factors that can induce epigenetic change. [119]
Human leukocyte antigen-DRB1*15 haplotype is a potential risk factor of MS. Because of the increased likelihood of the mother's human leukocyte antigen-DRB1*15 allele being passed onto their children, this contributes to the instances of MS being more prevalent from the mother. HLA-DRB1 is thought to be regulated via epigenetic means. The correlation of MS and this allele is speculated to be due to the presence of hypomethylation in the CpG island of HLA-DRB1, and those that carry the allele tend to exhibit this hypomethylation. HLA-DRB1 exon 2 is a particular region where evidence has shown that methylation is shown to be important in regulation. Research has furthered the evidence that variation in HLA-DRB1 DMR, which is a mechanism that is methylation regulated, that in turn regulates increased HLA-DRB1 expression, displays an increased risk for MS, and the exhibition of the disease. [119] [120]
Higher levels of expression of specific types of miRNA are often seen in the brain of those afflicted, showing an association of these types of miRNA and MS. Higher expression of miR-155 and miR-326 is often associated with CD4+T cell differentiation, and with this differentiation, instances of autoimmune encephalitis occur, which is the link with which it is thought that smoking can induce epigenetic changes that increase susceptibility to MS. Higher expression levels of miR-18b, miR-493, miR-599, and miR-96 are often seen in patients diagnosed with MS. miR-145 detection appears to be a promising future diagnostic tool due to its high specificity of 90% and sensitivity of 89.5% in whole blood testing due to its capability of distinguishing healthy patients versus those with MS. A symptom associated with MS patients is white matter lesions in the brain, and these lesions when biopsied showed higher expression of miR-155, miR-326 and miR-34a. These are especially notable due to the fact that overexpression of these miRNA's cause downregulation of CD47, leading to myelin phagocytosis, because of CD47's role of inhibiting macrophage activity. [121]
MS patients can be identified through observation of abnormal DNA methylation patterns in genes responsible for inflammation and myelination factor expression. Methylation occurs in the genomic region, CpG island, and is imperative in regulation of transcription. A methylated CpG region typically is the mechanism that will silence a gene, whereas a hypomethylated region is able to induce transcription. Using methylation inhibitors it has been shown that allowing higher proliferation of T cells can be achieved by preventing silencing. Abnormalities in methylation patterns increase the generation of CD4+T auto reactive. Hypomethylation of CpG regions of the PAD2 gene, a regulator of MBP which in turn regulates myelin, is also associated with higher instances of MS. This hypomethylation leads to overexpression of the PAD2 gene. These patterns have been observed in the white matter of patients with MS. While methylation is an indicator of MS, its effects are more specialized to location in MS, for example, where these patterns are observed in white matter. [121]
Association of abnormal histone modification in MS patients can be found in lesions located in the brain, with most instances of this being observed in patients over time and in lesions located in the frontal lobe. Higher instance of histone acetylation can be seen in patients afflicted over time, but this is counteracted by lower instances of histone acetylation in lesions found on the brain early in the course of the disease. The mechanisms by which histone modifications work in the progression of MS are unconfirmed, but changes in acetylation are often associated with the disease.
Trichostatin
Positive responses were observed in animal trials utilizing this HDAC inhibitor, associated with mediation of inflammatory pathways and thus resulting in lower instances of inflammatory responses in the brain. It was also shown to be effective in decreasing levels of disability when the mice were in a relapsing stage of MS. Trichostatin's mediation of symptoms is not well known but is thought to work in increasing acetylation at the H3 and H4 histones in CD4+T cells where MS patients often display differences in acetylation levels at these histones that control patients do not.
Vorinostat
Animal trials were utilized along with the testing of human myeloid dendritic cells. Not much is known about the mechanisms of vorinostat; however regulation of Th1/Th17 cytokine expression, which are responsible for inducing inflammation, were observed, thereby decreasing instances of inflammation and demyelination. Decreased patterns of T cell proliferation were also observed, similar to how trichostatin mediates disease symptoms. [122]
Valpropic acid
Valpropic acid has been shown to have positive results in animal trials, in the mitigation of the disease by regulating the severity and duration of MS. Its mechanism is decreasing the presentation of miRNA. Its mechanism for such has been observed in rats by shifting Th1 and Th17 to Th2 (responsible for inducing inflammation), thereby downregulating miRNA expression in inflammatory cytokines, tumor mediating mechanisms, and the spine. This is another instance in which T cell expression regulation is present, by preventing proliferation through interference of its pathway, similar to trichostatin and vorinostat. Another effect of VPA is its prevention of macrophage and lymphocyte proliferation in the spinal cords of MS rats. Currently, no HDAC inhibitors are in use for the mitigation of symptoms in MS patients; however, some are in pre-clinical trials at this time. [121]
In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.
Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.
In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.
Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.
While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.
In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of diabetes patients may help to elucidate otherwise hidden causes of this disease.
The epigenetics of schizophrenia is the study of how inherited epigenetic changes are regulated and modified by the environment and external factors and how these changes influence the onset and development of, and vulnerability to, schizophrenia. Epigenetics concerns the heritability of those changes, too. Schizophrenia is a debilitating and often misunderstood disorder that affects up to 1% of the world's population. Although schizophrenia is a heavily studied disorder, it has remained largely impervious to scientific understanding; epigenetics offers a new avenue for research, understanding, and treatment.
Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.
Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications.
Epigenetics of physical exercise is the study of epigenetic modifications to the cell genome resulting from physical exercise. Environmental factors, including physical exercise, have been shown to have a beneficial influence on epigenetic modifications. Generally, it has been shown that acute and long-term exercise has a significant effect on DNA methylation, an important aspect of epigenetic modifications.
Human herpes viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.
Epigenetics of depression is the study of how epigenetics contribute to depression.
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.
Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.
Epigenetic effects of smoking concerns how epigenetics contributes to the deleterious effects of smoking. Cigarette smoking has been found to affect global epigenetic regulation of transcription across tissue types. Studies have shown differences in epigenetic markers like DNA methylation, histone modifications and miRNA expression between smokers and non-smokers. Similar differences exist in children whose mothers smoked during pregnancy. These epigenetic effects are thought to be linked to many of negative health effects associated with smoking.
Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.
Epigenetic priming is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons and tumor-suppressor gene activation in cancer treatment respectively.
Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.
Epigenetics of chronic pain is the study of how epigenetic modifications of genes affect the development and maintenance of chronic pain. Chromatin modifications have been found to affect neural function, such as synaptic plasticity and memory formation, which are important mechanisms of chronic pain. In 2019, 20% of adults dealt with chronic pain. Epigenetics can provide a new perspective on the biological mechanisms and potential treatments of chronic pain.