Sex, Epilepsy, and Epigenetics

     When referring to epilepsy, we are referring to a heterogeneous group of disorders, including both those of genetic origin and those acquired. They are associated with a number of pathogenic mechanisms, seizure manifestations, comorbidity profiles and therapeutic responses. It has been observed through clinical and translation research that many of these epileptic features are closely affect by sex differences, especially hormones. That is, there is emerging evidence that common pathological features in epilepsy syndrome are linked with sex differences with males exhibiting a greater incidence than females. Through this paper, Qureshi et al, explain the primary epigenetic mechanisms and how these are now being used to integrate hormonal and genetic influences at molecular, cellular and network levels in epileptic disorders and the process of epilptogenesis (described in previous post).

“The foremost epigenetic mechanisms include DNA methylation (and hydroxymethylation), histone protein post-translational modifications (PTMs) and higher-order chromatin remodeling, and noncoding RNA (ncRNA) regulation. These multilayered processes are highly interconnected and exert their regulatory effects through coordinate actions.”

     Epigenetic mechanisms are mediator of the brains form and function and it believed to be a source in the promotion of dimorphism in the brain and body. They help establish and maintain sex differences in gene expression, for example the X inactivation-specific transcript (XIST) and genomic imprinting (more details related to its function in paper). Various epigenetic factors are expressed in sex-specific patterns in the breain known to be dimorphic, however these factors and there mechanisms are sensitive to sex steroid hormone pathways and exposure. Sex modulation has also been observed in autosomally encoded factors. “These observations suggest that epigenetic regulators in brain are deployed in a sex-specific manner, consistent with other evidence from expression quantitative trait loci analyses revealing sex-biased gene regulatory architectures in human brain.”

     Qureshi et al. describe various non-mutually exclusive paradigms relating epigenetic factors and neurological diseases including: : mutations in genes encoding epigenetic factors that cause disease, genetic variation in genes encoding epigenetic factors modifying disease risk, and the expression and function of epigenetic factors targeting disease-associated genomic loci, gene products, and cellular pathways. The first has proven to be true linking DNA methylation and histone modifying enzymes with the onset of the disease. Emerging data on the second paradigm has demonstrated variability in the vulnerability to epileptic disorders, like for example polymorphisms of the bromodomain-containing protein 2 (BRD2) gene which confers susceptibility to common forms of myoclonic epilepsy. This has also been studied in mice, demonstrating a sex-specific decrease in seizure thresholds. Lastly, evidence indicating that an increase in DNA methylation in the hippocampus are associated with epileptogenesis and that adenosine exhibit inhibition of DNA methylation (described in previous post), supports the third paradigm.

     The observations detailed throughout the paper suggest that the epigenetic factors and mechanisms in males and females underlie sex differences associated with risk, onset, and progression of epileptic disorders. However, seeing as many bodily functions work in coaction it is important to study other pathways and how these interact with both epigenetic factors and epilepsy. In this way, it might be possible to generate a novel therapeutic drug to treat these and other diseases more efficiently.

Reference: Qureshi, I.A., Mehler, M., (July 4, 2014). Sex, Epilepsy and Epigenetics. Elsevier, Retrieved from http://ac.els-cdn.com/S0969996114001831/1-s2.0-S0969996114001831-main.pdf?_tid=7ae5413c-bdc7-11e6-a331-00000aacb361&acdnat=1481257694_2ef9836c0fdfbf1053537c6b34baff56

New Differentially Expressed Genes and Differential DNA Methylation Underlying Refractory Epilepsy

Over 65 million people are affected with epilepsy worldwide. A variety of genetic and environmental factors have been associated with epilepsy and seizures. In the case of epilepsy, DNA methylation has been deemed one of the principal epigenetic mechanisms leading to epilepsy. These affect genomic reprograming, tissue-specific gene expression and global gene silencing without affecting the sequence. 

It has been seen that many of these DNA methylations are present at the promoters of genes, resulting in a decrease of gene expression. Besides promotors, an inverse relationship between gene expression and DNA methylation has been seen in exons and introns. Not only has it been discovered that selective changes in genome-wide DNA methylation and increased DNA methyltransferase are associated with temporal lobe epilepsy (TLE), but also that ketogenic diets could attenuate seizure progression though DNA methylation. 

The work of Xi Liu et al. was focused on analyzing the pattern of genome wide DNA methylation and gene expression using methylated DNA immunoprecipitation linked with sequencing. As a result, they were able to distinguish a new pattern of DNA methylation associated with refractory epilepsy patients. They also found that there was no significant difference between epileptic samples and controls in genome, CpG, CHG, and CHH coverage distribution and that differentially methylated regions were discovered on all genes except for the male Y chromosome. Generally, no significant relationship in modulation was found between DNA methylation and gene expression. Xi Liu et al, also working towards generating DNA methylation and gene expression profiles to prove the relationship between DNA methylation and gene expression via distribution of hyper-, hypo- and unmethylated gene expression levels in different elements.

     The importance of this paper is that is the first genome wide report on DNA methylation and gene expression in refractory epilepsy patients. Over 62 differentially expressed genes were found to be correlated with epilepsy and seizures. However, the similarity in results between epileptic samples and the controls indicated no significant difference in global DNA methylation and gene expression. That is, the change in DNA methylation in the study is no corresponded with alterations in gene expression.

Reference: Liu, X., Ou, S., Xu, T., Liu, S. Yuan, J., Huang, Y., Qin, L., Yang, H., Chen, L., Tan, X., Chen, Y., (November 26,2016), New Differentially Expressed Genes and Differential DNA Methylation Underlying Refractory Epilepsy. Oncotarget. Retrieved from http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=13642

“MicroRNA epigenetic signatures” (Piletic & Kunej, 2016) in epilepsy

        Post-translational modifications in epigenetics, such as methylation and acetylation, have always been discussed, but on the other hand, the active role of microRNAs (miRNAs) has not been explained in such detail. miRNAs are short non-coding RNAs that participate as regulators of gene expression. Klara Piletic and Tanja Kunej describe 63 miRNA genes that are epigenetically regulated in association with 21 diseases, such as cardiovascular disease, rheumatoid arthritis, autism, gastric, cervical, ovarian, prostate and bladder cancer. Temporal lope epilepsy (TLE) is included in these diseases.

          MiRNAs are approximately 22 nucleotides long, and there are currently more than 460 human miRNAs known.  They are transcribed by RNA polymerase II (Pol II). miRNAs target messenger RNAs (mRNAS) and degrade them. miRNA is non coding RNA, that is transcribed and is exported from the nucleus. It is then cut by a Dicer protein down to 22 nucleotides and then loaded into the Argonaut complex, where it can inhibit gene translation and act to degrade other RNAs.

http://www.nature.com/leu/journal/v26/n3/images/leu2011344f1.jpg

In temporal lobe epilepsy, the following miRNAs genes are epigenetically regulated: miR-27a, miR-193a-5p, miR-486, miR-618, miR-133a-1, miR-151, miR-191, miR-375, miR-411, miR-342, miR-34a, miR-627 and miR-576. Patients that suffer from TLE, “can display hippocampal sclerosis, which is a histopathologic abnormality including segmental neuron loss as well as other changes” (2016). DNA hyper methylation plays a major role in this condition, but so does miRNA, that “plays a role in the pathophysiology of TLE” (2016).  

           

References:

Piletic, K. & Kunej, T. (2016). MicroRNA epigenetic signatures in human disease. Archives of Toxicology, 90(2405-2419). 

Epileptogenesis: Can the science of epigenetics give us answers?

Due to the complex progression of epilepsyand the multiple inherited and acquired factors that have influence on the onset and progression of this disease, developing cures for this disroder has proved to be challenging, with current treatment have focused on controlling seizure activity. Epigenetic mechanisms like DNA and histone modifications may contribute to epileptogenesis. Aberrant epigenetic patterns have already been identified in a number of central nervous system disorders like schizophrenia and Alzheimer disease, and this also includes epilepsy. It is still up to debate if the epigenetic changes are the cause or the result of many diseases. Here, we will discuss some recent findings suggesting that epileptogenesis alters the epigenetic landscape after seizures.

Seizure activity results in gene expression changes, including alterations in mRNA levels for GluR2 and bdnf (epileptogenesis-related genes). Following seizures in an animal model, histone acetyltransferases (HATs) mediated histone acetylation at the promoter regions of both genes, which could result in a higher expression of these genes. On the other hand, HDAC (histone deacetylase) inhibitors have been used as treatment for neurological disorders such as epilepsy. There has been evidence of hypermethylation  of the reelin promoter in association with temporal lobe epilepsy (TLE). Supporting this, there is increased expression of DNMT (DNA methyltransferase) in the neurons from the temporal neocortex of TLE patients. Histone methylation, like DNA methylation, may also play a role in epileptogenesis. The JARID1C histone demethylase is associated with X-linked mental retardation and in a minority of epilepsy patients. Also, as histone methylation is critical for memory formation, abnormal regulation of this methylation may lead to cogitive decline, which is associated with epilepsy. Some transcriptional activators recruit epigenetically related co-activators and repressors that influence chromatin restructuring. For example, the transciptional factor CREB and nuclear factor-kB are activated after a seizure and associate with HAT proteins to remodel chromatin. The transcription factor REST has also been implicated in the regulation of several epileptogenesis specific factors, like growth factors, neurotransmitter receptors, and ion channels. These finding suggest that there is a possibility of developing epigenetic based drug therapy. For example, VPA is a drug treatment used for epilepsy and was recently discovered to have HDAC inhibitory properties.

For more information, you can read the paper cited here:

Lubin, F. D. (2012). Epileptogenesis: can the science of epigenetics give us answers?. Epilepsy Currents, 12(3), 105-110.

“Epigenetics: Impacts on Disease Susceptibility and Pharmacotherapy” (Abubakar & Haque, 2016) in epilepsy

        Scientists have learned from epigenetics that the hereditary material that compromises all living beings, can be modified by simple and complex mechanisms, that can change completely the way it is expressed. Based on this, “genes that are linked to other diseases apart from cancer can be identified, silenced or activated using drugs or diets in order to treat the disease aetiology (or causes).” (2016)

        Since epigenetics is “involved in the control of the central nervous system and memory regulation” (2016), it has a tremendous impact on neurological disorders, such as epilepsy. This impact is made through regulation of ”genes responsible for signal transduction, inflammation, cell metabolism, ion transport, synaptic transmission, and stress” (2016). In the case of epilepsy, DNA methylation is increased in promoter regions found in temporal lobe epilepsy (TLE). This kind of epilepsy is the most common form with focal seizures. This may result in loss or trouble with memory, due to the function of the temporal lobe related to the creation of memories. The left temporal lobe is important for verbal memories, such as learning names or remembering facts for a test. Epilepsy in the left temporal lobe can cause problems remembering names and finishing sentences. The right temporal lobe is important for visual memories, such as remembering the face of another person or remembering how to get to a particular place (Epilepsy Society, 2015). Additional to hyper methylation in the promoter sequence of the temporal lobe, it has also been found in the Reelin DNA promoter. Reelin (RELN) is a large protein produced in the brain that triggers nerve cells through a signaling pathway in order to migrate them to their proper locations (Genetic Home References). “Reelin may also regulate synaptic plasticity, which is the ability of connections between neurons (synapses) to change and adapt over time in response to experience” (Genetic Home References). By over methylation of the gene that codes for the reelin protein, the proper connections between neurons cannot happen in the brain and therefore, communication is lost. “Once Reelin is silenced epigenetically, granule cell dispersion will be emerged causing epilepsy.” (Abubakar & Haque, 2016)

        Whenever someone’s been diagnosed with a health or neurological condition, the first question that arises is “can it be treated or cured?” Drugs used for treatment involving epigenetics, do not halt these epigenetic processes, but instead, correct the ketogenesis (Abubakar & Haque, 2016). There are various drugs for epigenetic pharmacotherapy, such as Vidaza, Zolinza and Vorinostat. They are divided by two classes: DNA methyltransferase inhibitors (Vidanza) and histone deacetylase inhibitors (Zolinza/Vorinostat) (Abubakar & Haque, 2016). As discussed previously on another post, a ketogenic diet with low fat, low carbohydrate, and high content, has been proven to decrease gene methylation. Similarly, these drugs also inhibit gene methylation, but on the other hand, they also promote acetylation. Another drug that works in the same way is imipramine. “DNAdemethylase removes the methyl group in the genome, and the methyl groups on the histone moiety are removed by histone demethylase. Therefore, induction of these enzymes through diet or pharmaco­therapy is likely to improve gene expression.” (Abubakar & Haque, 2016)

References:

(2015, August). How epilepsy can affect memory. Retrieved from https://www.epilepsysociety.org.uk/how-epilepsy-can-affect-memory

(2016, December). RELN gene. Retrieved from https://ghr.nlm.nih.gov/gene/RELN

Abubakar, A. & Haque, M. (2016) Epigenetics: Impact on Disease Susceptibility and Pharmacotherapy. Indian Journal of Phamaceutical Education and Research, 50(310-321). 

Study proves that “the administration of an anti-convulsive ketogenic diet is associated with gene regulating DNA methylation changes in rat TLE” (Kobow et al., 2013).

In epilepsy, it is shown that there is an increase, rather than a loss, of DNA methylation. The ketogenic diet (KD) is based on a high-fat and low-carbohydrate diet that acts as an anti-epileptic therapy.

It is recognized to work well in both humans and animal models, since it is well known that both, diet and environmental changes, play a very important role in the epigenome.  This diet was used by investigators, led by Katja Kobow, to examine methylation in the CpG islands of rats that are positive for temporal lobe epilepsy (TLE) (2013).  

In this study, the TLE rats were fed with a standard ketogenic diet, while strictly controlling body weight. Apart from the control group rats, the experimental group rats were prepared by inserting through brain surgery, a continuous video-electroencephalography monitor for studying of the brain before, during and after a seizure. DNA methylation profiling was made via examination of the extracted hippocampal tissue (2013). The investigators used Methyl-capture and massive parallel sequencing (Methyl-Seq) for analysis of this genomic DNA methylation. This was backed up by examination of mRNA (mRNA-Seq) sequencing from the same tissue.

The ketogenic diet was proven to regulate gene expression by modifying chromatin structure, by altering DNA methylation. Results showed that KD did not have a significant impact in the severity or duration of a clinical seizure, but it did however, affect the seizure frequency per week, by reducing those (2013). As mentioned before, epilepsy is related to hyper DNA methylation, but on the contrary, the KD diet was proven to “reduce DNA methylation at gene bodies as well as intronic and exonic regions.” (2013)

The KD, is “a well-recognized anti-epileptic treatment in children with severe and chronic epilepsy that delays chronification of the disease and partially rescues the DNA methylation and corresponding gene expression phenotype” (2013). This diet “interferes with aberrant seizure-related genomic and locus specific alterations in DNA methylation and gene expression” (2013). In this study, “both hyper- and hypomethylation events were detected with subsequent gene repression or activation” (2013).  It is not known exactly how the KD diet works to reduce DNA methylation and reduce the patient’s seizures. This study opens the doors for further epileptic analysis through epigenetics, in order to better understand and hopefully discover a new and better anti-seizure therapy.

References:

Kobow, K. et al. (2013) Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathologica, 126(741-756). 

Access:

http://link.springer.com/article/10.1007/s00401-013-1168-8

EPILEPSY AWARENESS

Epigenetic Mechanisms in Stroke and Epilepsy

     DNA and histone methylation cause epigenetic remodeling which represents central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing and memory formation. Recent studies have discovered that chromatin modifications have significant roles in neurodegenerative diseases associated with ischemic stroke and epilepsy via the activation of REST, a gene silencing transcription factor which leads to epigenetic remodeling of transcriptionally responsive targets implicated in neuronal death.

References:
Hwang, J., Aromolaran, K., Zukin, R.S. (2013). Epigenetic Mechanisms in Stroke and Epilepsy.
Retrieved from http://www.nature.com/npp/journal/v38/n1/pdf/npp2012134a.pdf

The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine

     Epilepsy is one of the most prevalent neurological condition characterized by spontaneously non-provoked seizures that occur as a result of a complex disorder of network homeostasis. Current treatments focus on the suppression of these epileptic seizures. However, research has come across evidence for the prevention of epileptogenesis (development and progression of epilepsy) through biochemical manipulations. Detlev Boison, in his review, The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine has discussed this concept via the mechanisms implicated in epileptogenesis and the biochemical interactions between adenosine and glycine which serve as mayor contributors to the development of epilepsy.

     Boisin focuses on temporal lobe epilepsy (TLE), especially its key metabolites adenosine and glycine.  These are primitive biological elements with important biochemical functions, whose homeostasis is generally affected in epileptic brains. Adenosine is an endogenous anticonvulsant and seizure terminator only when the adenosine A1 receptors is activated. Overexpression of its kinase (ADK), results in an adenosine deficiency associated with the increase of astrocytes, known as astrogliosis, and the adenosine receptor (AR) has been linked to the control of DNA methylation under the activity of ADK. The latter is expressed in both cytoplasmic and nuclear isoforms whose functions range from homeostatic regulation to modification in DNA methylation statuses. Astrogliosis is closely related with the increase in ADK expression and the deficiency of adenosine, which leads to the production of seizures and the hypermethylation of DNA. Therefore, it can be concluded that the dysregulation of ADK has a significant effect in the process of turning a normal brain into an epileptic one. Glycine, on the other hand, may have various effects depending on the activation of its presynaptic or postsynaptic receptor (GlyR’s). Low concentrations of glycine have pro-convulsive effects, while high concentrations reduce its occurrence. Its homeostasis is crucial in maintaining a balance in neuronal excitability and its regulation and reuptake is achieved by the glycine transporter 1 (GlyT1). The latter, when increased, is associated with TLE and has been considered a promising target for treatments of cognitive diseases.  

     “The knowledge of epigenetic mechanisms implicated in the development of epilepsy provides a conceptual and mechanistic framework for the future development of epigenetic therapies tailored to prevent epilepsy (antiepileptogenic) or its progression (disease modifying)”(Boison, 2016). The current treatments fail to take into account the causes of epilepsy and are therefore unable to halt epileptogenesis, which is why epigenetic modifications offer new therapeutic alternatives. Using rat models it has been discovered that an adenosine augmentation can effectively reduce and even suppress the occurrence of seizures. They have also been used to form the basis for both the ADK hypothesis (acute insults to the brain such as traumatic brain injury, seizures, or a stroke lead to an acute surge in adenosine associated with transient downregulation of ADK) and the methylation hypothesis of epileptogenesis (suggests that seizures may induce epigenetic modifications aggravating the condition). Alteration in DNA methylation plays a significant role in in the development and progression of neurodegenerative diseases like epilepsy. The increased activity of DNA methylating enzymes and the hypermethylation of DNA has been linked to onset of epilepsy. However, the status of DNA methylation depends on the equilibrium of biochemical enzyme reactions catalyzed by DNA methyltransferases (DNMTs) or Ten-eleven translocations (TET) enzymes. These mechanisms depend on transmethylation pathways controlled by adenosine and glycine concentrations regulated by ADK and GlyT1.

     The biochemical discoveries discussed by Boison have made way for new research areas. Understanding the epigenetics behind epilepsy may be result in the development of novel and effective therapeutic strategies.

 “Challenges for drug development remain. It needs to be determined whether new therapeutic agents can enter the brain and whether a higher level of selectivity for specific isoforms of ADK can be achieved. Due to the different distribution of nucleoside transporters within the brain there might be opportunities for the development of cell-type or isoform selective therapies.” (Boison, 2016).

References:

Boison, D. (2016). The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829603/pdf/fnmol-09-00026.pdf

Diving deeper: some epigenetic changes in epilepsy

The establishment and maintenance of epigenetic marks are crucial for normal development and function. Here, we will discuss how DNA methylation patterns are altered, and the presence od certain histone variants and microRNA's is changed in epilepsy. 

DNA Methylation

There is evidence in recent studies in animal models and tissues from epileptic patients that have revealed altered methylation patterns in DNA in these patients, compared to healthy individuals. 

An autopsy study of the hippocampus tissue from patients with temporal lobe epilepsy found a greater degree of methylation of the reelin promoter among the patients with epilepsy compared to controls (Kobow et al., 2009). Reelin is an extracellular matrix protein that performs key functions in neuronal migration, synaptic plasticity, and maintenance of the laminar structure of hippocampal granule cells. Loss of this structure in the hippocampal dentate nucleus (granule dispersion) is present in up to 50% of the patients affected by temporal lobe sclerosis. 

Additionally, another study examined DNMT1 and DNMT3A (DNA methyltransferase 1 and 3A) expression in patients with temporal lobe epilepsy compared to healthy controls. Remember that DNMT1 is responsible for the maintenance of methylation patterns, and DNMT3a and DNMT3b were involved in de novo methylations. The study concluded that both DNMT’s are more abundant in patients with temporal lobe epilepsy, hinting that they may contribute to the pathogenesis of this type of epilepsy (Zhu et al., 2011).

Finally, a study analyzed the overall DNA methylation in the hippocampus of rats with chronic epilepsy compared with controls. The group with chronic epilepsy showed more overall methylation (Kobow et al., 2013). But when provided with a ketogenic diet, they observed a reduction in seizure frequency and a change in the DNA methylation pattern.

Histone modification

Studies in animal models have demonstrated changes in chromatin mediated by histone modifications following epileptic seizures. 

For example, a study analyzed rat hippocampal tissue 3 hours after having induced status epilepticus and found that histone H4 hypoacetylation (which is a marker for gene repression) in the promoter of the glutamate 2 receptor (GluR2), as well as hyperacetylation (a marker for gene transcription) in the brain-derived neurotrophic factor (BDNF) promoter (Huang et al., 2002). These findings clearly show that status epilepticus* rapidly triggers modulations in histone acetylation. The same study found that prior administration of an HDAC (histone deacetylase) inhibitor prevented hyperacetylation of the GluR2 promoter, which could help design a treatment for epilepsy. 

In a more recent study, the same author reported greater HDAC2 expression in tissue from patients with temporal lobe epilepsy, as well as from animal subjects with status epilepticus, than in controls (Huang et al., 2011). HDAC2 is a type of HDAC expressed by the central nervous system that is active in neurodevelopment. Results from the study show that HDAC2 is significantly involved in the pathogenesis of temporal lobe epilepsy, and in the cognitive impairment that may sometimes also be associated with this type of epilepsy.

In another animal model of epilepsy using electrically induced seizures, Tsankova et al. found changes in the acetylation of histones H3 and H4 at the CREB promote region in the rat hippocampus, with H4 hypoacetylation of CREB and H3 hyperacetylation of CREB miRNA (Tsankova et al., 2004). CREB is an important transcriptional factor that plays an important role in the epileptogenic process. 

Micro-RNA and epilepsy

Several studies of the expression profile of miRNA in epilepsy have been published recently, and they offer promising information about the potential role of miRNA as a biomarker.

One example is a study that describes the miRNA expression profile in rats with induced status epilepticus based on analyses of brain tissue and blood samples (Liu et al., 2009). The authors found similar expression profiles for one miRNA subtype in blood and hippocampal tissue and therefore support the possibility that miRNA's might serve as blood biomarkers for epilepsy.

On the other hand, studies of miRNA are also providing additional knowledge about the epileptogenic process.

For example, various studies carried out in animal models have all shown increased expression of miRNA-132 in the hippocampus of rats with induced status epilepticus  (Pulido et al., 2015). It is understood that miRNA-132 has anti-inflammatory functions, and inflammation has been shown to play a role in epileptogenesis. Therefore, increased miRNA-132 may contribute to the development of epilepsy.

                                                        

*Status epilepticus is said to occur when a seizure lasts too long or when seizures occur close together and the person doesn't recover between seizures. 

More information can be found in this paper:

Pulido Fontes, L., Quesada Jimenez, P., & Mendioroz Iriarte, M. (2015). Epigenetics and epilepsy. Neurología (English Edition), 30(2), 111-118. http://dx.doi.org/10.1016/j.nrleng.2014.03.002

Basic epilepsy knowledge

What is epilepsy? 

Epilepsy is a central nervous system disorder (neurological disorder) in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness (Mayo Clinic). Seizure symptoms can vary widely, from low to high intensity. Difficulty breathing and temporary confusion, are also symptoms related to epilepsy.

Who gets affected by epilepsy and what are the causes?

People of any age can get affected by epilepsy, especially if there is any structural brain lesion. It is, however, more common in young children and older people. The disorder can be developed through life or be present since birth. Car accidents, falling, gun shots, pregnancy complications and emotional issues can affect or cause epilepsy. Additional factors such as health conditions, age, and race can make its development more likely. For example, it is more common in people with Hispanic backgrounds.  

How is epigenetics involved in epilepsy?

The methylation hypothesis of epileptogenesis (development and progression of epilepsy) suggests that changes in DNA methylation are implicated in the progression of the disease. In particular, global DNA hypermethylation appears to be associated with chronic epilepsy (Boison, 2016). 

Can it be treated or cured? 

Currently, there are no cures for epilepsy, but instead the seizures and symptoms are controlled by specific medications. Fortunately, epigenetic influences in epilepsy are being studied, and since epigenetic changes are reversible, there may be an answer in the near future. 


For more information, 

http://perspectivesinmedicine.cshlp.org/content/5/12/a022731.long

Source:
http://america.aljazeera.com/watch/shows/techknow/blog/2014/3/5/this-is-your-brainoncannabidiol.html

Epigenetics and Epilepsy

"Epilepsy is a chronic disorder, the hallmark of which is recurrent, unprovoked seizures (...) The human brain is the source of human epilepsy. Although the symptoms of a seizure may affect any part of the body, the electrical events that produce the symptoms occur in the brain. The location of that event, how it spreads and how much of the brain is affected, and how long it lasts all have profound effects. These factors determine the character of a seizure and its impact on the individual. Essentially, anything the brain can do, it can do in the form of a seizure." (Sirven, 2014)

 http://natrave.cz/files/images/epilepsie.jpg

The following link introduces a peer-reviewed paper about the chronic disorder: 

Epigenetics and epilepsy by Avtar Roopra, Raymond Dingledine & Jenny Hsieh


For more information about Epilepsy, the Epilepsy Foundation is there to help!
http://www.epilepsy.com/

Exploring Epilepsy

Photo of the Day

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Epigenetics Glossary of Terms

It is very important to understand some of the concepts used highly in the epigenetics field. Some of them are presented in the following link:

http://www.zymoresearch.com/learning-center/epigenetics/glossary

Coming up...

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First Quiz!

It's easy to access, just by clicking the following link:

https://goo.gl/forms/s9D18alEESWrFdAG3

Epigenetics: A Primer

Photo and information taken from: http://images.the-scientist.com/content/images/articles/58007/epigenetics_primer.jpg

The Histone Code

     First, it is important to start with the basics of DNA organization. The eukaryotic genome is organized in what is known as a nucleosome, the first level of condensation. The nucleosome is composed of 147 base pairs of negatively-charged DNA wrapped twice around an octamer of positively-charged proteins called histones. It consists of two H2A and H2B dimers, and a H3 and H4 tetramer. The nucleosomes are separated by 1,016 base pairs (bp) of  DNA called "linker DNA'',  which constitutes an arrangement referred to as ''beads on a string'', that is around 10nm in diameter. DNA can be further condensed at different points during the cell cycle, forming a 30nm chromatin fiber composed of packed nucleosomes using the histone H1, which binds to the linker DNA. These 30nm fibers can form scaffolds and further condense until chromosomes are formed, which are the highest form of DNA organization within a cell.

     Histones have very dynamic N-terminal ''tails'' extending from the surface of the nucleosome that are rich in basic amino acids. These tails can be modified by post-translational modifications (PTM's) catalyzed by a variety of enzymes, by adding either methyl, acetyl or phosphoryl groups. Aditionally, lysines can be mono, di or tri-methylated, while arginine can accept up to two methyl groups which adds to the complexity.  Methylation of DNA at cytosine residues, as well as PTMs of histones, including phosphorylation, acetylation, methylation and ubiquitylation, contributes to the epigenetic information carried by chromatin. These changes play an important role in the regulation of gene expression by modulating the access of regulatory factors to the DNA. Many modification sites are close enough to each other and it seems that modification of histone tails by one enzyme might influence the rate and efficiency at which other enzymes use the newly modified tails as a substrate.
These modifications seem to be part of a complex scheme where distinct histone modifications act in a sequential manner or in combination to form a “histone code”, read by other proteins to control the structure and/or function of the chromatin fiber.

"The different histone modifications act either in a sequential manner or in combination to form a “histone code",  which is read by other proteins to bring about the specific biological events."

   

   
The so-called histone code is established and maintained by post-translational writers, which are the enzymes that modify the histones post translationally. These modifications can be "read" by post-translational readers, which are the motifs that recognize the histones based on their modification state. Modifications of histones, give signals that are recognized by specific binding proteins, or ''readers'' which can influence gene expression and chromatid organization. Examples of readers will be discussed later on.

     One example of writers are histone acetyltransferases (HATs) and histone deacetylases (HDAC's), responsible for the addition and removal of acetyl groups, respectively. On the other hand, methylation is carried out by histone methyltransferases (HMTs), divided in two classes: K-HMT if it methylates lysine, or arginine (R-HMT). Methylation is a stable modification, unlike acetylation and phosphorylation, which makes it an ideal mark for long-term maintenance of chromatin structure. The existence of histone demethylases (HDMTs, or DNMTs) that counteract the methylations of histones in the cell is unclear. Phosphorylation of histones H1 and H3 is known to  play important roles in both transcriptional regulation and  mitosis, and it has been found that ubiquitination is critical in mitotic and meiotic growth. Finally, biotinylation is a new PTM of histones that has been identified, carried out by biotinidase and holocarboxylase synthetase (HCS).

     The acetylation of lysine weakens the DNA-histone interactions, destabilizing the nucleosome by making it less positively charged. This results in DNA that is more weakly bound to the nucleosome, facilitating the binding of transcription factors to DNA. But histone marks by themselves may not alter the nucleosomal dynamics, which might be brought on by binding of further non-histone proteins.

    While hyperacetylation is linked to gene expression, deacetylation can be related to silencing. Methylation is not as straight-forward, as H3-K9 (histone 3, lysine 9) and can be associated to inactive genes. However. H3-K4 methylation is seen in both active and silenced regions, since trimethylation is specific for active state of transcription, whereas dimethylated K4 exists in both active and repressive genes. The site and the number of methyl groups are both important for biological consequences of these modifications. Additionally, in mammals, DNA methylation is controlled by DNMT1, DNMT3a and DNMT3b enzymes. DNMT1 is involved in de novo methylation, while DNMT3a and DNMT3b are linked to the maintenance of methylation.


''Modified histone tails provide recognition sites for factors involved in either the activation or repression of gene expression.''


     Errors in PTMs of histones and other epigenetic marks may be involved in diseases, which is why it's critical to understand these modifications, as it promises new ways to treat several diseases. Certain modifications can either promote, limit, or have no effect on the depositions of other modifications. The combination of these can regulate in a direct or indirect manner, the state of chromatin organization and gene expression.


More information about the histone code, the following article can help:

Munshi, A., Shafi, G., Aliya, N., & Jyothy, A. (2009). Histone modifications dictate specific biological readouts. Journal of Genetics and Genomics, 36(2), 75-88.

It can be downloaded from:
https://www.researchgate.net/publication/24030126_Histone_modifications_dictate_specific_biological_readouts

Things to know

"The lifestyle choices you make today affect not only you but also your children and grandchildren. In other words, each of us has far greater responsibility than we ever imagined!" (Dr. Frank Lipman, 2016) 

http://www.drfranklipman.com/faqs-on-epigenetics/

http://res.cloudinary.com/jpress/image/fetch/w_620,f_auto,ar_3:2,c_fill/http://www.berwickshirenews.co.uk/webimage/1.3897071.1443098886!/image/490011200.jpg

From DNA to proteins

Photo of the Day: The Art of Epigenetics

https://redice.tv/a/i/n/06/92epigenetic.jpg

Epigenetics: How does it work?

Why hasn't Epigenetics been heard before? It is probably because it wasn't detected until recently and also because it is a field still in discovery. Epigenetics does not alter the sequence of DNA, so how is it heritable? The epigenetic modifications are the mechanisms by which most living beings are different. These include DNA methylations (or addition of a methyl group); post-translational histone modifications, such as methylation, acetylation, ubiquitination and phosphorylation; chromatin remodeling; histone variants and noncoding RNAs. These concepts will be introduced very soon, but first it is really important to understand what histones are, how are they related to DNA and the processes involved in the formation of proteins from DNA.

For more more informations about histones:
http://www.whatisepigenetics.com/histone-modifications/

http://202.97.205.78/hhmd/Images/histone_modifications_big.jpg

An introduction to epigenetics in just four minutes!

The Beginning: unraveling the mystery

"Mystery creates wonder, and wonder is the basis of a man’s desire to understand.” – Neil Armstrong

Epigenetics is a field of biology which encompasses much that is still uncovered, however let us begin with what we do know and search for the answers hidden beneath. The beginning of our mystery was brought to light by Conrad Waddington in 1942. His concept of epigenetics was one used to describe the existence of mechanisms of inheritance that went above or over the standard genetic norm.

This branch of genetics explains the manner in which external factors may influence our genes not only today, but also in our future generations. According to this, the saying “you are what you eat” is epigenetically correct, and the importance of the role the environment plays in our lives has reached an even higher level. None the less, how does our environment play an epigenetic role? What does it mean to influence our genes, and what kind of influence are we speaking of?

To begin, let’s set an example of the difference between genetics and epigenetics where we relate these two terms to a good book. Genetics would then take the role of the text. All genes would become the words that have been written and make the book what it is. In every copy of the book, the same text is printed; the same words are transcribed. However, not all readers understand the same thing. The story could be interpreted a million different ways and, in a sense, all of them would be correct. In similar fashion, epigenetics permits the different interpretations of the text (genes) which results in distinct readings. In other words, epigenetics is the different punctuation marks that control the context of genes.

These marks, which are mitotically heritable, help regulate gene expression by silencing or activating genes. As mentioned before, they do not change the genome sequence but rather influence it through various modifications such as: histone variants, histone modifications, chromatin binding, etc. These will be explained soon. Welcome to a world brimming with mysteries waiting to be unraveled.



Written by: Gabriela Matos Maldonado