Epigenetics and depression: current challenges and new ...

1 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is and depression : current challenges and newtherapeutic optionsMarc Schroedera, Marie O. Krebsb, Stefan Bleichaand Helge FrielingaIntroductionThe Global Burden of Disease Study predicted majordepression to become the second leading cause ofdisability until 2020, and the lifetime prevalence wasestimated to be approximately 17% in the United States,with similar rates being reported on the European level[1]. Major depressive disorder (MDD) displays a varietyof psychopathological symptoms and diverse clinicalmanifestations with at least depressed mood and/or aloss of interest or pleasure as core symptoms. Additionalsymptoms encompass changes regarding weight, appe-tite, sleep, psychomotor and thinking disturbances withexcessive worrying, guilt, and possibly suicidal ideation[2]. Although there exist numerous hints toward a neu-robiological understanding of depression [3] and environ-mental effects such as adverse life events merged into amodel of gene environment interactions (G E), theystill do not provide the required answers concerningindividual risk assessment, history of disease, andpharmacological or psychological treatment options [4].

2 Therefore, the epigenetic perspective may add newinsights into the G E findings that were shown to beapplicable to depression . Caspietal.[5] were the first tosuggest that it might be applicable to depression . Theyshowed that childhood maltreatment and later stressfullife events predicted the onset of depressive symptomsonly in genetically predisposed individuals with a short(s) allele of the serotonin transporter promoter poly-morphism (5-HTTLPR), while the long allele carrierswere more resilient to depression after adverse lifeevents. Moreover, incidences of childhood maltreatmentwere found to be predictive for adult depression onlyamong s allele rat, Weaveretal. [6] first showed that differences inmaternal care can lead to less fearful offspring raised bywell-caring mothers and more fearful offspring raised bylow tactile stimulating mothers. These distinct behaviorscan be traced back to epigenomic changes in the hippo-campal glucocorticoid receptor gene, through differenthistone acetylation and DNA methylation, which wereaDepartment of Psychiatry, Social Psychiatry andPsychotherapy, Hannover Medical School, Hannover,Germany andbUniversity Paris Descartes, Faculty ofMedicine Paris Descartes, Paris, FranceCorrespondence to Professor Dr Helge Frieling, MD,Department of Psychiatry, Social Psychiatry andPsychotherapy, Hannover Medical School,Carl-Neuberg-Str.

3 1, 30625 Hannover, GermanyTel: +49 511 532 6559; fax: +49 511 532 2415;e-mail: Opinion in Psychiatry2010, 23:588 592 Purpose of reviewEpigenetics comprises heritable but concurrent variable modifications of genomic DNAdefining gene expression. The aim of this publication is to review the field of epigeneticsin depression . Within this scope, we outline potential therapeutic options evolving in thisyoung field of psychiatric findingsRecently published papers show that epigenetic mechanisms like histone modificationsand DNA methylation affect diverse pathways leading to depression -like behaviors inanimal models. Adverse alterations of gene expression profiles, including glucocorticoidreceptor or brain-derived neurotrophic factor, were shown to be inducible by early lifestress and reversible by epigenetic drugs. Postmortem studies revealed epigeneticchanges in the frontal cortex of depressed suicide victims. There exists profoundevidence for histone deacetylase inhibitors to be a novel line of effectiveantidepressants via counteracting previously acquired adverse epigenetic of the complex causal factors leading to depression , Epigenetics is ofconsiderable interest for the understanding of early life stress in depression .

4 The currentresearch regarding epigenetic pharmaceuticals is promising and deserves furtherattention in depression and psychiatry in general, and may strike out new ways towardsindividually tailored , DNA methylation, Epigenetics , homocysteine, treatmentCurr Opin Psychiatry 23:588 592 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins0951-73670951-7367 2010 Wolters Kluwer Health | Lippincott Williams & Lippincott Williams & Wilkins. Unauthorized reproduction of this article is by cross-fostering or by the infusion of ahistone deacetylase (HDAC) inhibitor (HDACi). Thisfirst proof of behavioral programming of the epigenomedue to early life stress was shown to be reversible not onlyduring the first weeks of life, but also in adulthood,through the application of the amino acid methionine,which serves as a donor for methyl groups in DNAmethylation [7]. Thus, epigenetic mechanisms are notonly essential for normal cellular development, differen-tiation, and a nonmutagenic tissue-specific translation ofthe genome, but also may serve as a novel and promisingapproach to psychiatric present review focuses on the latest developmentsin the field of Epigenetics with respect to to only a limited number of articles published withinthe last 18 months, we also refer to earlier pioneeringpublications regarding this topic for further reading.

5 Thelatest literature of special interest in the field of epige-netics and depression comprises nine papers publishedbetween February 2009 and April 2010. They are brieflysummarized and discussed in the respective context of aneurobiological approach to depression , early life stressand abuse research, brain-derived neurotrophic factor(BDNF), homocysteine and potential epigenetic of epigenetic regulation in thegenomeEpigenetics comprises mechanisms of gene expressionmodifications that do not alter the genomic code , these mechanisms are epi , which meansalongside the coding sequence of the genome consistingof the four nucleobases adenine, guanine, thymine, andcytosine. Besides the sequence of nucleobases in thegenome, gene expression in different types of cells andtissues is modulated by two major mechanisms that arecurrently crucial for the understanding of Epigenetics inpsychiatric disorders. The first is DNA methylation ,which means that the expression of a gene is silencedthrough the modification of the gene s promoter region,which initiates the transcription of the adjacent methylation of promoter cytosines in repetitivedinucleotide sequences of cytosines and guanines(CpG) allows further methyl-CpG binding proteins, likemethyl CpG-binding protein 2 (MeCP2), to bind andrepress expression of the gene [8].

6 Secondly, epigeneticmarking is achieved through physical changes in theformation of tightly packed DNA, which is normallyfolded into nucleosomes around proteins, so-calledhistones. These can be modified through either acety-lation, methylation, or phosphorylation at their NH2-termini, which may lead to an unfolding of the DNA/histone unit. This formation allows the transcription ofthe genomic DNA and subsequent protein state of packaging of DNA through histones andtherefore the accessibility of DNA in different tissues isheritable and known as the Histone code [9]. Althoughepigenetic marking is heritable, it is not stable through-out the lifespan, and interactions between enzymesmediating either DNA methylation, DNA methyltrans-ferases (DNMTs), or histone changes (HDACs) exist[10].Epigenomic stress memory through DNAmethylationThe early findings of maternal behavior determining thestress response in rats via epigenomic programming of theglucocorticoid receptor gene in the hippocampus wasrecently also shown to be true for humans.

7 The Meaney group [11 ] studied methylationsof the neuron-specific glucocorticoid receptor (NR3C1)promoter in hippocampi from suicide victims with andwithout a history of sexual and nonsexual child abusecompared with control subjects who had died from causesother than suicide and had not been abused as level of DNA methylation at the NR3C1 promotersites was significantly higher in the hippocampi of abusedsuicides compared with nonabused and control receptor expression measured by theamount of mRNA was also found to be reduced inhippocampi of abused suicide victims compared withnonabused and control subjects. Due to previous findingsshowing an association of decreased hippocampal gluco-corticoid receptor expression with depression [12] andthe heritability of the epigenome, the authors interpretedtheir findings as an indicator for a possible parent-to-offspring transmission of depression via an epigeneticmodification of stress recent study conducted by Murgatroydetal.

8 [13 ]investigated early life stress and DNA methylation of thearginine vasopressin (AVP) gene enhancer region and itsconsequences regarding MeCP2 occupancy in the hypo-thalamic paraventricular nucleus. The separation of new-born mice pups from their mothers for the first 10postnatal days resulted in a persistent upregulation ofAVP due to hypomethylation of theAVPgene enhancerregion. As AVP increases the release of corticotropin-releasing hormone (CRH) inducing a sustained hyper-activity of the hypothalamic pituitary adrenal (HPA)axis, early stressed mice showed deficits in the forced-swim test and in step-down avoidance learning behavioral and cognitive deficits were partlyreversible by an AVP receptor antagonist. A furtherinteresting finding was that the hypomethylation of theAVPgene enhancer region remained unchanged despiteintermediate behavioral changes due to short-term AVPreceptor blockade. Furthermore, MeCP2 as a possibleconnection between different epigenetic mechanisms isEpigenetics and depressionSchroederetal.

9 589 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is to restore previously stress-affected DNAhypomethylation through recruiting DNMTs. Thereby,MeCP2 might help to protect DNA methylation patternsover time [14 ].A recent study conducted by Danielsetal.[15 ] founddifferences in plasma corticosterone and hippocampalnerve growth factor levels in a rat pup separation modelbut no changes in methylation patterns of the exon 17glucocorticoid receptor promoter in the without epigenetic alterations, behavioral differ-ences between early stressed and control rats wereobserved shortly after the completion of separation inan open field neurotrophic factorThe transcription of theBDNF gene was previouslyshown to be regulated by epigenetic modifications invol-ving DNA methylation, MeCP2 and chromatin remodel-ing [16]. According to the neurotrophin hypothesis ofdepression, BDNF expression is decreased in depressionand stress states.

10 This hypothesis could be tested on theepigenomic level in a mouse chronic defeat stress was shown that the down-regulation of BDNF mes-senger RNA (mRNA) was accompanied by long-lastinghistone dimethylation (leading to gene suppression) inthe hippocampus [17].Recently, Rothetal.[18 ] reportedBDNF gene silencingin the prefrontal cortex (PFC) of early maltreated rat pupsdue to DNA methylation processes that lasted into adult-hood (postnatal day 90). Furthermore, offspring derivedfrom maltreated females exhibited the same abusivebehaviors as their mothers and greater DNA methylationin the PFC and hippocampus, indicating a generation-to-generation transmission of previously acquired DNAmethylation patterns. Interestingly, further cross-foster-ing experiments showed no significant change in DNAmethylation patterns, in the direction of either mal-treated offspring to normally caring mothers or normallytreated offspring to maltreating mothers.