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

Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment

[EN] Postsynaptic alpha(2A)-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for alpha(2)-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs). We studied the effect of antipsychotic (AP) treatment in AP-free (n = 12) and AP-treated (n = 12) subgroups of schizophrenia subjects and in rats acutely and chronically treated with typical and atypical antipsychotics. ADRA2A mRNA expression was selectively upregulated in AP-treated schizophrenia subjects (+93%) whereas ADRA2C mRNA expression was upregulated in all schizophrenia subjects (+53%) regardless of antipsychotic treatment. Acute and chronic clozapine treatment in rats did not alter brain cortex Adra2a mRNA expression but increased Adra2c mRNA expression. Both ADRA2A and ADRA2C promoter regions showed epigenetic modification by histone methylation and acetylation in human DLPFC. The upregulation of ADRA2A expression in AP-treated schizophrenia subjects might be related to observed bivalent chromatin at ADRA2A promoter region in schizophrenia (depicted by increased permissive H3K4me3 and repressive H3K27me3) and could be triggered by the enhanced H4K16ac at ADRA2A promoter. In conclusion, epigenetic predisposition differentially modulated ADRA2A and ADRA2C mRNA expression in DLPFC of schizophrenia subjects.This work was supported by Spanish MINECO (grant SAF2013-48586-R) and Basque Government (grant IT1211/19). The authors would like to thank the staff members of the Basque Institute of Legal Medicine for their cooperation in the study

Opposite Alterations of 5¬HT2A Receptor Brain Density in Subjects with Schizophrenia: Relevance of Radiotracers Pharmacological Profile

The status of serotonin 5HT2A receptors (5HT2ARs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5HT2AR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3 H]lysergic acid diethylamide (LSD) and the antagonist [ 3 H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (Bmax) and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3 H]LSD binding. However, [3 H] MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3 H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increased functional activity of brain cortical 5-HT2ARs in schizophrenia.This study was supported by the Spanish State Research Agency, Ministry of Science and ERD Funds (SAF-2009-08460, SAF-2017-88126-R, RYC-2017-22412 and CTQ-2017-87637-R), and the Basque Government (SAIOTEK S-PE13UN019 and IT-1211-19). Part of this work was conducted under the Maria de Maeztu Units of Excellence Programme (Grant MDM-2017-0720). C.M. and A.G.-B. were recipients of fellowships from the Marie Slodowska-Curie Programme (European Union’s Horizon 2020, Grant 747487) and the Basque Government predoctoral training Programme, respectivel

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