RESUMO
Despite the fact that tryptophan (Trp) is an essential amino acid that humans typically obtain through diet, there are several interesting tryptophan dynamics at play in the body. Quantifying and understanding these dynamics are crucial in studies of depression, autism spectrum disorder, and other disorders that involve neurotransmitters directly synthesized from tryptophan. Here we detail the optimization of waveform parameters in fast scan cyclic voltammetry at carbon fiber microelectrodes to yield four-fold higher sensitivity and six-fold higher selectivity compared to previously reported methods. We demonstrate the utility of our method in measuring (1) exogenous Trp dynamics from administration of Trp to PC-12 cells with and without overexpression of tryptophan hydroxylase-2 and (2) endogenous Trp dynamics in pinealocyte cultures with and without stimulation via norepinephrine. We observed interesting differences in Trp dynamics in both model systems, which demonstrate that our method is indeed sensitive to Trp dynamics in different applications.
RESUMO
The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.
Assuntos
Encéfalo/metabolismo , Proteína de Ligação a CREB/genética , Proteínas do Citoesqueleto/metabolismo , Proteína p300 Associada a E1A/genética , Células-Tronco Embrionárias/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Cromatina/química , Feminino , Genômica , Células HEK293 , Heterozigoto , Humanos , Masculino , Camundongos , Neurônios/metabolismo , Ligação Proteica , Domínios Proteicos , Proteômica , Ativação TranscricionalRESUMO
Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.
RESUMO
Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR's role in synaptic transmission may be complex-specific. To better understand their roles in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs (eEPSCs), however, the effects of mTORC1 on eEPSCs were postsynaptic and the effects of mTORC2 were presynaptic. Despite postsynaptic inhibition of evoked release, mTORC1 inactivation enhanced spontaneous vesicle fusion and replenishment, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.
Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neurônios/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Proteína Regulatória Associada a mTOR/metabolismo , Transmissão Sináptica/fisiologia , Animais , Cálcio , Membrana Celular , Feminino , Regulação da Expressão Gênica , Imuno-Histoquímica , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Proteína Regulatória Associada a mTOR/genética , Vesículas SinápticasRESUMO
The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.
Assuntos
Glioma/enzimologia , Glioma/genética , Histonas/metabolismo , Criança , Ativação Enzimática , Inativação Gênica , Histonas/genética , Humanos , Lisina/metabolismo , Metilação , Complexo Repressor Polycomb 2/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismoRESUMO
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG. METHODS AND MATERIALS: A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items "diffuse intrinsic pontine glioma" and 221 articles using search items "diffuse brainstem glioma radiotherapy." Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT. RESULTS: We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months. CONCLUSIONS: As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.
RESUMO
As the process that silences gene expression ensues during development, the stage is set for the activity of Polycomb-repressive complex 2 (PRC2) to maintain these repressed gene profiles. PRC2 catalyzes a specific histone posttranslational modification (hPTM) that fosters chromatin compaction. PRC2 also facilitates the inheritance of this hPTM through its self-contained "write and read" activities, key to preserving cellular identity during cell division. As these changes in gene expression occur without changes in DNA sequence and are inherited, the process is epigenetic in scope. Mutants of mammalian PRC2 or of its histone substrate contribute to the cancer process and other diseases, and research into these aberrant pathways is yielding viable candidates for therapeutic targeting. The effectiveness of PRC2 hinges on its being recruited to the proper chromatin sites; however, resolving the determinants to this process in the mammalian case was not straightforward and thus piqued the interest of many in the field. Here, we chronicle the latest advances toward exposing mammalian PRC2 and its high maintenance.
Assuntos
Epigênese Genética , Regulação da Expressão Gênica , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Animais , Cromatina/metabolismo , Humanos , Mutação , Neoplasias/genética , Neoplasias/fisiopatologia , Transporte Proteico , Pesquisa/tendênciasRESUMO
A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
Assuntos
Neoplasias do Tronco Encefálico/patologia , Cromatina/química , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Complexo Repressor Polycomb 2/antagonistas & inibidores , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/metabolismo , Células Cultivadas , Criança , Cromatina/genética , Cromatina/metabolismo , Modelos Animais de Doenças , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/patologia , Glioma/genética , Glioma/metabolismo , Humanos , Camundongos , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismoRESUMO
Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.
Assuntos
Neoplasias Encefálicas/genética , Deleção de Genes , Duplicação Gênica , Proteínas Musculares/genética , Proteínas Nucleares/genética , Pinealoma/genética , Ribonuclease III/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Criança , Proteínas do Citoesqueleto , RNA Helicases DEAD-box/genética , Metilação de DNA , Exoma , Genoma Humano , Homozigoto , Humanos , Pessoa de Meia-Idade , Glândula Pineal/patologia , Domínios Proteicos , TranscriptomaRESUMO
Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis.
Assuntos
Isocitrato Desidrogenase/genética , Fatores de Transcrição SOXB1/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X/genética , Animais , Apoptose , Astrocitoma/metabolismo , Astrocitoma/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Fator de Ligação a CCCTC/metabolismo , Diferenciação Celular , Células Cultivadas , Metilação de DNA , Epigênese Genética , Humanos , Isocitrato Desidrogenase/metabolismo , Camundongos , Camundongos SCID , Gradação de Tumores , Invasividade Neoplásica , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Interferência de RNA , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Proteína Nuclear Ligada ao X/antagonistas & inibidores , Proteína Nuclear Ligada ao X/metabolismoRESUMO
High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.
Assuntos
Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Criança , Glioma/genética , Glioma/metabolismo , Humanos , Gradação de Tumores , PrognósticoRESUMO
Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica/genética , Proteínas/metabolismo , Animais , Comportamento Animal/fisiologia , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto , Feminino , Perfilação da Expressão Gênica , Técnicas de Inativação de Genes , Genótipo , Células HEK293 , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas/genética , Fatores de Transcrição , UbiquitinaçãoRESUMO
Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, whole-brain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that large-scale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)--a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.
Assuntos
Axônios/patologia , Conectoma , Imageamento por Ressonância Magnética , Rede Nervosa , Doenças do Sistema Nervoso , Transtornos Psicóticos , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Transtornos Psicóticos/patologia , Transtornos Psicóticos/fisiopatologiaRESUMO
Multiple circuitries ensure that cells respond correctly to the environmental cues within defined cellular programs. There is increasing evidence suggesting that cellular memory for these adaptive processes can be passed on through cell divisions and generations. However, the mechanisms by which this epigenetic information is transferred remain elusive, largely because it requires that such memory survive through gross chromatin remodeling events during DNA replication, mitosis, meiosis, and developmental reprogramming. Elucidating the processes by which epigenetic information survives and is transmitted is a central challenge in biology. In this review, we consider recent advances in understanding mechanisms of epigenetic inheritance with a focus on histone segregation at the replication fork, and how an epigenetic memory may get passed through the paternal lineage.
Assuntos
Cromatina/genética , Replicação do DNA , Epigênese Genética , Histonas/metabolismo , Animais , Humanos , Padrões de Herança , Masculino , Proteínas do Grupo Polycomb/genética , EspermatogêneseRESUMO
An issue of increasing theoretical and translational importance is to understand the conditions under which learned fear can be suppressed, or even eliminated. Basic research has pointed to extinction, in which an organism is exposed to a fearful stimulus (such as a context) in the absence of an expected aversive outcome (such as a shock). This extinction process results in the suppression of fear responses, but is generally thought to leave the original fearful memory intact. Here, we investigate the effects of extinction during periods of memory lability on behavioral responses and on expression of the immediate-early gene c-Fos within fear conditioning and extinction circuits. Our results show that long-term extinction is impaired when it occurs during time periods during which the memory should be most vulnerable to disruption (soon after conditioning or retrieval). These behavioral effects are correlated with hyperactivation of medial prefrontal cortex and amygdala subregions associated with fear expression rather than fear extinction. These findings demonstrate that behavioral experiences during periods of heightened fear prevent extinction and prolong the conditioned fear response.
Assuntos
Tonsila do Cerebelo/fisiologia , Extinção Psicológica/fisiologia , Medo/psicologia , Lobo Frontal/fisiologia , Memória/fisiologia , Rede Nervosa/fisiologia , Animais , Comportamento Animal/fisiologia , Interpretação Estatística de Dados , Imuno-Histoquímica , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
BACKGROUND: A key finding from recent studies of epigenetic mechanisms of memory is that increasing histone acetylation after a learning experience enhances memory consolidation. This has been demonstrated in several preparations, but little is known about whether excitatory and inhibitory memories are equally sensitive to drugs that promote histone acetylation and how transcriptional changes in the hippocampal-medial prefrontal cortex network contribute to these drug effects. METHODS: We compare the long-term behavioral consequences of systemic, intrahippocampal and intra-medial prefrontal cortex administration of the histone deacetylase inhibitor sodium butyrate (NaB) after contextual fear conditioning and extinction 1 and/or 14 days later in male c57BL/6J mice (n = 302). Levels of histone acetylation and expression of the product of the immediate-early gene c-Fos were assessed by immunohistochemistry following infusion of NaB into the hippocampus (n = 26). RESULTS: Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared to the effects on initial memory formation. NaB administered following weak extinction induced behavioral extinction, infralimbic histone acetylation and c-Fos expression consistent with strong extinction. No similar effect was seen in the prelimbic cortex. The involvement of the infralimbic cortex was confirmed as infusions of NaB into the infralimbic, but not prelimbic cortex, induced extinction enhancements. CONCLUSIONS: These studies show that the memory modulating ability of drugs that enhance acetylation is sensitive to a variety of behavioral and molecular conditions. We further identify transcriptional changes in the hippocampal-infralimbic circuit associated with extinction enhancements induced by the histone deacetylase inhibitor NaB.
Assuntos
Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Córtex Pré-Frontal/metabolismo , Acetilação , Animais , Butiratos/farmacologia , Condicionamento Psicológico , Modelos Animais de Doenças , Genes Precoces/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Histonas/efeitos dos fármacos , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/metabolismo , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories.