Epigenetika helburu duten sendagaiak

“Epigenetics” refers to any change in genetic activity without altering DNA sequence. Non-genetic factors (i.e. infections and drugs) may cause epigenetic alterations throughout our genome, indicating which gene will be expressed and which one will not. Therefore, epigenetics is the linker between genetics and environmental factors and experiences. Exposure to non-genetic factors at crucial stages of development (fetal development, early childhood and adolescence), would establish our epigenome through 3 mechanisms: DNA methylation, post-translational histone modifications and non-coding RNA. There have been many studies in the field of epigenetics in the last decades, the most studied epigenetic mechanism being posttranslational histone acetylation. Alterations on histone acetylation pattern have been related to the development of many diseases. The most notable example is cancer. Based on this, histone deacetylase inhibitors (HDACi) became new targets in oncological therapy. Nowadays, four HDACi are approved for the treatment of different types of cancer, and more than 20 HDACi are being evaluated in clinical phase. The efficacy of HDACi against cancer has leveraged the study of HDACi in other diseases. Due to the complexity and the lack of effective treatment for neurological and psychiatric disorders, HDACi drugs have become an interesting potential therapy. Due to neuroprotective properties of HDACi agents, their effectiveness against Huntington´s and Parkinson’s diseases is being evaluated. HDACi research around bipolar disorder and schizophrenia is also moving forward.; Epigenetika hitzak DNA-sekuentzia aldatu gabe aktibitate genetikoan gertatzen den edozein aldaketari egiten dio erreferentzia. Faktore ez-genetikoek (hala nola, infekzioak eta farmakoak) aldaketa epigenetikoak eragin ditzakete, gure genoma osotik zein gene adieraziko diren eta zein ez erabakiz. Hortaz, epigenetika genetikaren eta inguruko faktoreen eta esperientzien arteko lokailua da. Garai erabakigarrietan (garapen fetalean, haurtzaro goiztiarrean eta nerabetasunean) eraginez, faktore ez-genetikoek gure epigenoma ezarriko lukete, deskribatu izan diren 3 mekanismoren bidez: DNAren metilazioa, histonen itzulpen osteko aldaketak eta RNA ez-kodetzaileen eragina. Azken hamarkadetan, epigenetikaren inguruko ikerketa ugari egin dira; gehien aztertu den mekanismo epigenetikoa itzulpen osteko histonen azetilazioa izan da. Azetilazio-asaldurak hainbat gaixotasunen garapenarekin erlazionatu dira. Horren adibiderik aipagarriena minbizia izan da. Horretan oinarrituz, histonen deazetilasen inhibitzaileak (HDACi) minbiziaren kontrako tratamendu gisa postulatu ziren. Gaur egun, lau HDACi daude onartuta minbizi-mota ezberdinen aurkako tratamendurako, eta 20 baino gehiago fase klinikoan ebaluatzen ari dira. HDACi-ek minbizian duten eraginkortasunak beste gaixotasun batzuetan aztertzeko aukera eman du. Gaixotasun neuroendeka- tzaile eta psikiatrikoen konplexutasuna eta tratamendu eraginkorren falta dela eta, HDACi-ak terapia potentzial interesgarri bihurtu dira. HDACi-ek eragile neurobabesle gisa joka dezaketenez, Huntingtonen eta Parkinsonen gaixotasunetan duten eraginkortasuna aztertzen ari da. Asaldura bipolarrean eta eskizofrenian ere aurrera doa HDACi-en ikerketa

Permissive epigenetic regulatory mechanisms at the histone level are enhanced in postmortem dorsolateral prefrontal cortex of individuals with schizophrenia

Background: Susceptibility to schizophrenia is determined by interactions between genes and environment, possibly via epigenetic mechanisms. Schizophrenia has been associated with a restrictive epigenome, and histone deacetylase (HDAC) inhibitors have been postulated as coadjuvant agents to potentiate the efficacy of current antipsychotic drugs. We aimed to evaluate global histone posttranslational modifications (HPTMs) and HDAC expression and activity in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Methods: We used postmortem DLPFC samples of individuals with schizophrenia and controls matched for sex, age, and postmortem interval. Schizophrenia samples were classified into antipsychotic-treated or antipsychotic-free subgroups according to blood toxicology. Expression of HPTMs and HDAC was quantified by Western blot. HDAC activity was measured with a fluorometric assay. Results: H3K9ac, H3K27ac, and H3K4me3 were globally enhanced in the DLPFC of individuals with schizophrenia (+24%–42%, p < 0.05). HDAC activity (−17%, p < 0.01) and HDAC4 protein expression (−20%, p < 0.05) were downregulated in individuals with schizophrenia. Analyses of antipsychotic-free and antipsychotic-treated subgroups revealed enhanced H3K4me3 and H3K27ac (+24%–49%, p < 0.05) and reduced HDAC activity in the antipsychotic-treated, but not in the antipsychotic-free subgroup. Limitations: Special care was taken to control the effect of confounding factors: age, sex, postmortem interval, and storage time. However, replication studies in bigger cohorts might strengthen the association between permissive HPTMs and schizophrenia. Conclusion: We found global HPTM alterations consistent with an aberrantly permissive epigenome in schizophrenia. Further studies to elucidate the significance of enhanced permissive HPTMs in schizophrenia and its association with the mechanism of action of antipsychotic drugs are encouraged

Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects

Abstract Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2R and mGlu3R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3R ligands in clinical trials. Studies evaluating mGlu2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2R and mGlu3R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3R, but not mGlu2R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2R, but not mGlu3R regulation observed in schizophrenia brains. mGlu2R and mGlu3R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2R and mGlu3R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3R, but not mGlu2R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3R expression are activated to counterbalance mGluR loss of function is described