Epigenetic Mechanisms Mediate Nicotine-Induced Reward and Behaviour in Zebrafish

2021 ◽  
Vol 19 ◽  
Author(s):  
Maria Paula Faillace ◽  
Ramón O. Bernabeu
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epigenetic Regulation ◽  
Histone Deacetylases ◽  
Dna Methyltransferase ◽  
Dopamine Neurons ◽  
Epigenetic Mechanisms ◽  
Chemical Modifications ◽  
Simultaneous Treatment ◽  
Polymerase Binding

: Nicotine induces long-term changes in the neural activity of the mesocorticolimbic reward pathway structures. The mechanisms involved in this process have not been fully characterized. The hypothesis discussed here proposed that epigenetic regulation participates in installing persistent adaptations and long-lasting synaptic plasticity generated by nicotine action on the mesolimbic dopamine neurons of zebrafish. The epigenetic mechanisms induced by nicotine entail histone and DNA chemical modifications, which have been described to lead to changes in gene expression. Among the enzymes that catalyze epigenetic chemical modifications, histone deacetylases (HDACs) remove acetyl groups from histones, thereby facilitating DNA relaxation and making DNA more accessible to gene transcription. DNA methylation, which is dependent on DNA methyltransferase (DNMTs) activity, inhibits gene expression by recruiting several methyl binding proteins that prevent RNA polymerase binding to DNA. In zebrafish, phenylbutyrate (PhB), an HDAC inhibitor, abolishes nicotine rewarding properties together with a series of typical reward-associated behaviors. Furthermore, PhB and nicotine alter long- and short-term object recognition memory in zebrafish, respectively. Regarding DNA methylation effects, a methyl group donor L-methionine (L-met) was found to dramatically reduce nicotine-induced conditioned place preference (CPP) in zebrafish. Simultaneous treatment with DNMT inhibitor 5-aza-2’-deoxycytidine (AZA) was found to reverse the L-met effect on nicotine-induced CPP as well as nicotine reward-specific impact on genetic expression in zebrafish. Therefore, pharmacological interventions that modulate gene expression epigenetic regulation should be considered a potential therapeutic method to treat nicotine addiction.

scholarly journals A Revolution in Dentistry: Epigenetics

2019 ◽  
Vol 07 (01) ◽  
pp. 001-005
Author(s):  
Namita Sepolia ◽  
Deepti Jindal ◽  
Sandhya Kaushwaha ◽  
Varun Jindal ◽  
Monika Negi
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cellular Proliferation ◽  
Cpg Islands ◽  
Odontogenic Tumors ◽  
Epigenetic Mechanisms ◽  
Epigenetic Changes ◽  
Daughter Cells ◽  
Aberrant Dna Methylation

AbstractEpigenetics is the study of potentially heritable changes in gene expression that does not involve changes in underlying DNA sequence. Epigenetic mechanisms play a crucial role in cellular proliferation, migration, and differentiation in both normal and neoplastic development. Epigenetic changes may be inherited and can occur during embryonal development or after birth. Once the change in DNA methylation takes place, following cell division the altered pattern is transferred into daughter cells by the action DNA methyltransferase enzyme, which recognizes hemi-methylated sites and methylates newly synthesized DNA formed during replication. Recently, it has been suggested that aberrant DNA methylation of cytosine-phosphate-guanine (CpG) islands is a common event in odontogenic tumors. Expression of DNA methyltransferase 1,3A,3B has been noted in various odontogenic tumors. Thus, this review aims to study the various epigenetic pathways that are altered in odontogenic tumors.

scholarly journals Epigenetic regulation of peroxiredoxins: Implications in the pathogenesis of cancer

2016 ◽  
Vol 242 (2) ◽  
pp. 140-147 ◽  
Author(s):  
Suet-Hui Ow ◽  
Pei-Jou Chua ◽  
Boon-Huat Bay
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Epigenetic Regulation ◽  
Histone Deacetylases ◽  
Epigenetic Mechanisms ◽  
Epigenetic Regulators ◽  
Future Treatments ◽  
Peroxiredoxin I ◽  
Reversible Nature

Peroxiredoxin I to VI (PRX I–VI), a family of highly conserved antioxidants, has been implicated in numerous diseases. There have been reports that PRXs are expressed aberrantly in a variety of tumors, implying that they could play an important role in carcinogenesis. Epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs have been reported to modulate expression of PRXs. In addition, the use of epigenetic regulators, such as histone deacetylases, has been demonstrated to restore PRX to normal levels, indicating that the reversible nature of epigenetics can be exploited for future treatments.

scholarly journals Dynamic changes in DNA methylation during seahorse (Hippocampus reidi) postnatal development and settlement

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Paula Suarez-Bregua ◽  
Sofia Rosendo ◽  
Pilar Comesaña ◽  
Lucia Sánchez-Ruiloba ◽  
Paloma Morán ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Postnatal Development ◽  
Expression Analysis ◽  
Epigenetic Regulation ◽  
Regulation Of Gene Expression ◽  
Age Groups ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanisms ◽  
Competent Larva

Abstract Introduction Most living marine organisms have a biphasic life cycle dependent on metamorphosis and settlement. These critical life-history events mean that a developmentally competent larva undergoes a range of coordinated morphological and physiological changes that are in synchrony with the ecological transition from a pelagic to a benthonic lifestyle. Therefore, transition from a pelagic to a benthonic habitat requires multiple adaptations, however, the underlying mechanisms regulating this process still remains unclear. Epigenetic regulation and specifically DNA methylation, has been suggested to be particularly important for organisms to adapt to new environments. Seahorses (Family Syngnathidae, Genus Hippocampus) are a fascinating group of fish, distinguished by their unique anatomical features, reproductive strategy and behavior. They are unique among vertebrate species due to their “male pregnancy”, where males nourish developing embryos and larvae in a brood pouch until hatching and parturition occurs. After birth, free-swimming offspring are pelagic and subsequently they change into a demersal lifestyle. Therefore, to begin to address the question whether epigenetic processes could be involved in the transition from a planktonic to a benthonic lifestyle observed in seahorses, we studied global DNA methylation profiles in a tropical seahorse species (Hippocampus reidi) during postnatal development and settlement. Results We performed methylation-sensitive amplified polymorphism (MSAP) along with quantitative expression analysis for genes suggested to be involved in the methylation machinery at six age groups: 1, 5, 10, 20, 30 and 40 days after male’s pouch release (DAR). Results revealed that the H. reidi genome has a significantly different DNA methylation profile during postnatal development and settlement on demersal habitats. Moreover, gene expression analysis showed up- and down-regulation of specific DNA methyltransferases (DNMTs) encoding genes. Conclusion Our data show that the differences in the DNA methylation patterns seen among developmental stages and during the transition from a pelagic to a benthonic lifestyle suggest a potential for epigenetic regulation of gene expression (through DNA methylation) in this species. Therefore, epigenetic mechanisms could be necessary for seahorse settlement. Nevertheless, if these epigenetic mechanisms come from internal or if they are initiated via external environmental cues should be further investigated.

Abstract 130: Hypercholesterolemia Suppresses Carotid Artery Endothelial NOS3 Expression via Epigenetic Mechanisms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Alex Sotolongo ◽  
Yi-Zhou Jiang ◽  
John Karanian ◽  
William Pritchard ◽  
Peter Davies
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Endothelial Cells ◽  
Dna Methyltransferase ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat

Objective: One of the first clinically detectable changes in the vasculature during atherogenesis is the accumulation of cholesterol within the vessel wall. Hypercholesterolemia is characterized by dysfunctional endothelial-dependent vessel relaxation and impaired NOS3 function. Since DNA methylation at gene promoter regions strongly suppresses gene expression, we postulated that high-fat/high-cholesterol diet suppresses endothelial NOS3 through promoter DNA methylation. Methods: Domestic male pigs were fed control diet (CD) or isocaloric high fat and high cholesterol diet (HC; 12% fat and 1.5% cholesterol) for 2, 4, 8 or 12 weeks prior to tissue collection. Furthermore, to determine the effects of risk factor withdrawal, an additional group of swine received HC for 12 weeks and then CD for 8 weeks; a control group received HC continuously for 20 weeks. Endothelial cells were harvested from common carotid aorta. In parallel in vitro studies, cultured human aortic endothelial cells (HAEC) were treated with human LDL, GW3956 (LXR agonist) and RG108 (DNA methyltransferase [DNMT] inhibitor). In cells from both sources, DNA methylation at the NOS3 promoter was measured using methylation specific pyro sequencing, and endothelial gene expression was measured using RT PCR. Results: HC diet increased plasma cholesterol level from 75 mg/dl on CD to a plateau of about 540 mg/dl within 2 weeks. Endothelial NOS3 expression was significantly reduced (71±9 % of CD) after 4 weeks of HC, a level sustained at subsequent time points. Withdrawal of HC for 8 weeks did not recover NOS3 expression. After 12-week HC, the NOS3 promoter was hypermethylated. Withdrawal of HC did not reverse NOS3 promoter methylation. In vitro treatment of HAEC with human LDL (200 mg/dl total cholesterol) or GW3956 (5μM) suppressed NOS3 mRNA to 50% and 30% respectively, suggesting that LXR/RXR is involved in suppression of NOS3. Nitric oxide production was consistently suppressed by GW3959. Both could be reversed through inhibition of DNMTs by RG108. Conclusions: DNA methylation and LXR/RXR pathway can mediate the HC-suppression of endothelial NOS3. The study identifies novel pharmaceutical targets in treating endothelial dysfunction. Crosstalk between these pathways is under investigation.

Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jessilyn Dunn ◽  
Haiwei Qiu ◽  
Soyeon Kim ◽  
Daudi Jjingo ◽  
Ryan Hoffman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Western Diet ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

scholarly journals Unraveling the functional role of DNA methylation using targeted DNA demethylation by steric blockage of DNA methyltransferase with CRISPR/dCas9

2020 ◽  
Author(s):  
Daniel M. Sapozhnikov ◽  
Moshe Szyf
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Region ◽  
Dna Methyltransferase ◽  
Dna Demethylation ◽  
New Method ◽  
Inducible Promoters ◽  
Specific Targeting ◽  
Main Effect

AbstractAlthough associations between DNA methylation and gene expression were established four decades ago, the causal role of DNA methylation in gene expression remains unresolved. Different strategies to address this question were developed; however, all are confounded and fail to disentangle cause and effect. We developed here a highly effective new method using only deltaCas9(dCas9):gRNA site-specific targeting to physically block DNA methylation at specific targets in the absence of a confounding flexibly-tethered enzymatic activity, enabling examination of the role of DNA methylation per se in living cells. We show that the extensive induction of gene expression achieved by TET/dCas9-based targeting vectors is confounded by DNA methylation-independent activities, inflating the role of DNA methylation in the promoter region. Using our new method, we show that in several inducible promoters, the main effect of DNA methylation is silencing basal promoter activity. Thus, the effect of demethylation of the promoter region in these genes is small, while induction of gene expression by different inducers is large and DNA methylation independent. In contrast, targeting demethylation to the pathologically silenced FMR1 gene targets robust induction of gene expression. We also found that standard CRISPR/Cas9 knockout generates a broad unmethylated region around the deletion, which might confound interpretation of CRISPR/Cas9 gene depletion studies. In summary, this new method could be used to reveal the true extent, nature, and diverse contribution to gene regulation of DNA methylation at different regions.

scholarly journals Haploinsufficiency of Dnmt1 Impairs Leukemia Stem Cell Function Through Derepression of Bivalent Chromatin Domains,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3459-3459
Author(s):  
Jennifer J. Trowbridge ◽  
Amit U. Sinha ◽  
Scott A. Armstrong ◽  
Stuart H. Orkin
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Dna Methyltransferase ◽  
Cell Function ◽  
Gene Signature ◽  
Conditional Knockout ◽  
Specific Gene ◽  
Epigenetic Mechanisms ◽  
Chromatin Domains ◽  
Hematopoietic Stem

Abstract Abstract 3459 Leukemia stem cells (LSCs) are an attractive target in treatment of many types of blood cancers. There remains an incomplete understanding of the epigenetic mechanisms driving LSC formation and maintenance, and how this compares to the epigenetic regulation of normal hematopoietic stem cells (HSCs). One of the major epigenetic modifications, DNA methylation, is catalyzed by the DNA methyltransferase enzymes Dnmt1, Dnmt3a and Dnmt3b. We observed decreased expression of Dnmt3a and Dnmt3b in LSCs isolated from a model of MLL-AF9-induced acute myeloid leukemia (AML) compared to normal HSCs. In contrast, expression of Dnmt1 was maintained in LSCs compared to HSCs, suggesting that Dnmt1 may have a critical function in the formation and maintenance of LSCs. Supporting this hypothesis, we found that conditional knockout of Dnmt1 fully ablates the development of AML. Furthermore, haploinsufficiency of Dnmt1 (Dnmt1fl/+ Mx-Cre) was sufficient to delay progression of leukemogenesis and impair LSC self-renewal. Strikingly, haploinsufficiency of Dnmt1 did not functionally alter normal hematopoiesis or HSCs, suggesting an enhanced dependence of LSCs on DNA methylation. Mechanistically, we observed that haploinsufficiency of Dnmt1 in LSCs resulted in derepression of genes that had been silenced by MLL-AF9-mediated transformation and marked by bivalent H3K27me3/H3K4me3 chromatin domains. These results suggest that the formation and maintenance of LSCs depends not only upon activation of a leukemogenic program, but also upon silencing of a specific gene signature that is active in HSCs through crosstalk between two epigenetic mechanisms, polycomb-mediated repression and DNA methylation-mediated repression. This silenced gene signature includes known and candidate tumor suppressor genes as well as genes involved in lineage restriction. These studies present evidence that distinct epigenetic regulatory mechanisms are dominant in LSCs compared to HSCs and provide novel gene candidates for targeted reactivation in AML therapy. Disclosures: Armstrong: Epizyme: Consultancy.

scholarly journals Is the effect of Decitabine limited to hypomethylation and DNMTs?

2019 ◽  
Author(s):  
Sina Dalvand ◽  
Amin Namdari ◽  
Ashraf Alemi ◽  
Mohammad Hassan Meshkibaf ◽  
Sam Setayesh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Histone Deacetylases ◽  
Dna Methyltransferase ◽  
Chromatin Condensation ◽  
Dna Demethylation ◽  
Histone Tails ◽  
Normal Cells ◽  
Before And After ◽  
Cancerous Cells

Abstract Background: Histone modifications play a crucial role in chromatin structure. Among enzymes, which regulate these processes, histone deacetylases (HDACs) can remove acetyl groups from histone tails, thus increasing their interaction with DNA and leading to chromatin condensation. 5-Aza-2′-deoxycytidine (AZad) or Decitabine is a potent hypomethylating agent that incorporates into DNA and traps DNA methyltransferase in the form of a covalent protein–DNA adduct. Azad, not only change the gene expression through demethylation of the gene's promoter, but it also can change gene expression independently from DNA demethylation. So, the present study was to distinguish whether AZad in addition to inhibitory effects on DNA methyltransferase, can change HDAC3 and HDAC7 mRNA expression in NALM-6, HL-60 cancer cell lines. Methods: HL-60, NALM-6 and normal cells were cultured, and the treatment dose of the AZad was obtained (1µM) by the MTT test. Finally, HDAC3 and HDAC7 mRNA expression were measured by Real Time PCR in HL-60 and NALM-6 cancerous cells before and after treatment. In addition, HDAC3 and HDAC7 mRNA expression in un-treated HL-60 and NALM-6 cancerous cells were compared to the normal cells. Results: Our result revealed that expression of HDAC3 and HDAC7, in HL-60 and NALM-6 cells increases as compared to normal cells. After treatment of HL-60 and NALM-6 cells with AZad, HDAC3 and HDAC7 mRNA expression were decreased significantly. Conclusions: Our data showed, the effects of AZad are not limited to direct hypomethylation of DNMTs but it can indirectly affect other epigenetic factors, such as HDACs activity, through converging pathways. Keywords: HDAC3 ; HDAC7 ; HL-60; NALM-6 ; Decitabine ; AZad

Epigenetics

2019 ◽  
pp. 56-70
Author(s):  
Edward Hookway ◽  
Nicholas Athanasou ◽  
Udo Oppermann
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Tumour Suppressor Genes ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

Regulation of adenosine A2Areceptor gene expression in a model of binge eating in the amygdaloid complex of female rats

2019 ◽  
Vol 33 (12) ◽  
pp. 1550-1561 ◽  
Author(s):  
Maria Vittoria Micioni Di Bonaventura ◽  
Mariangela Pucci ◽  
Maria Elena Giusepponi ◽  
Adele Romano ◽  
Catia Lambertucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Binge Eating ◽  
Epigenetic Regulation ◽  
Methylation Status ◽  
Amygdaloid Complex ◽  
Female Rats ◽  
Control Group ◽  
Compensatory Mechanism ◽  
Mrna Levels

Background:Pharmacological treatment approaches for eating disorders, such as binge eating disorder and bulimia nervosa, are currently limited.Methods and aims:Using a well-characterized animal model of binge eating, we investigated the epigenetic regulation of the A2AAdenosine Receptor (A2AAR) and dopaminergic D2 receptor (D2R) genes.Results:Gene expression analysis revealed a selective increase of both receptor mRNAs in the amygdaloid complex of stressed and restricted rats, which exhibited binge-like eating, when compared to non-stressed and non-restricted rats. Consistently, pyrosequencing analysis revealed a significant reduction of the percentage of DNA methylation but only at the A2AAR promoter region in rats showing binge-like behaviour compared to the control animals. Focusing thus on A2AAR agonist (VT 7) administration (which inhibited the episode of binge systemically at 0.1 mg/kg or intra-central amygdala (CeA) injection at 900 ng/side) induced a significant increase of A2AAR mRNA levels in restricted and stressed rats when compared to the control group. In addition, we observed a significant decrease in A2AAR mRNA levels in rats treated with the A2AAR antagonist (ANR 94) at 1 mg/kg. Consistent changes in the DNA methylation status of the A2AAR promoter were found in restricted and stressed rats after administration of VT 7 or ANR 94.Conclusion:We confirm the role of A2AAR in binge eating behaviours, and we underline the importance of epigenetic regulation of the A2AAR gene, possibly due to a compensatory mechanism to counteract the effect of binge eating. We suggest that A2AAR activation, inducing receptor gene up-regulation, could be relevant to reduction of food consumption.

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