The Effect Of Molecular Genetic Mechanisms On Drug Addiction And Related New Generation CRISPR Gene Engineering Applications

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Year-Number: 2021-2
Yayımlanma Tarihi: 2021-12-21 13:08:10.0
Language : English
Konu : Molecular biology and genetics
Number of pages: 50-60
Mendeley EndNote Alıntı Yap

Abstract

Drug addiction causes alterations in gene expression, synaptic function, and nerve flexibility in brain reward regions. Up to date improvements in genome editing technologies, suchlike the CRISPR-related endonuclease Cas9, have accelerated the development of neuroscience by rapidly and efficiently manipulating the endogenous genome of various cell types. CRISPR for the first time generated three epigenome editing platforms at the molecular, cellular, circuit-behavioral levels and performed single chromatin modifications on certain genes in specific cell populations. DNA methylation, histone modification and genes related to reward systems are effectors of the epigenome that have effects on the expression of small RNAs found in various pathways such as aging, memory, and cardiovascular disease. Previous attempts to alter one or more neurotransmitter receptors have had restricted achievement, and so far, no FDA-confirmed drugs are in hand to treat addiction disorders such as cannabis, methamphetamine, and cocaine use disorders. In the near future, clinically effective therapy could be possible with the CRISPR/Cas9 systems. The advancement of in vivo neural epigenome editing tools and administrations has been explored to reveal contribution of epigenetics to the pathophysiology of the brain. To date, the drugs that measure phenotypes and epigenetic effects are rather small, and further investigation of these effects is necessary to fully understand the outcomes of developmental exposure to drugs. In this review, we discussed how histone acetylation affects gene expression of brain reward pathways. Recent advances that contribute to drug addiction include epigenetic mechanisms and CRISPR/Cas9 systems to develop new therapeutics for future addiction treatments.

Keywords

Abstract

Drug addiction causes alterations in gene expression, synaptic function, and nerve flexibility in brain reward regions. Up to date improvements in genome editing technologies, suchlike the CRISPR-related endonuclease Cas9, have accelerated the development of neuroscience by rapidly and efficiently manipulating the endogenous genome of various cell types. CRISPR for the first time generated three epigenome editing platforms at the molecular, cellular, circuit-behavioral levels and performed single chromatin modifications on certain genes in specific cell populations. DNA methylation, histone modification and genes related to reward systems are effectors of the epigenome that have effects on the expression of small RNAs found in various pathways such as aging, memory, and cardiovascular disease. Previous attempts to alter one or more neurotransmitter receptors have had restricted achievement, and so far, no FDA-confirmed drugs are in hand to treat addiction disorders such as cannabis, methamphetamine, and cocaine use disorders. In the near future, clinically effective therapy could be possible with the CRISPR/Cas9 systems. The advancement of in vivo neural epigenome editing tools and administrations has been explored to reveal contribution of epigenetics to the pathophysiology of the brain. To date, the drugs that measure phenotypes and epigenetic effects are rather small, and further investigation of these effects is necessary to fully understand the outcomes of developmental exposure to drugs. In this review, we discussed how histone acetylation affects gene expression of brain reward pathways. Recent advances that contribute to drug addiction include epigenetic mechanisms and CRISPR/Cas9 systems to develop new therapeutics for future addiction treatments.

Keywords


  • Ajonijebu DC, Abboussi O, Russell VA, Mabandla MV, DanielsWMU (2017). Epigenetics: a link between addiction and socialenvironment. Cellular and Molecular Life Sciences. 74(15), 2735–2747. Doi: 10.1007/s00018-017-2493-1

  • Alam MA, Datta PK (2019). Epigenetic Regulation of ExcitatoryAmino Acid Transporter 2 in Neurological Disorders. Frontiersin Pharmacology. 10, 1510. Doi: https://doi.org/10.3389/fphar.2019.01510

  • Alegría-Torres JA, Baccarelli A, Bollati V (2011). Epigenetics andlifestyle. Epigenomics. 3(3), 267–277. Doi:10.2217/epi.11.22

  • Bastle RM, Neisewander JL (2016). Epigenetics and DrugAbuse.Recent Advances in Drug Addiction Research and Clinical Applications. 10.5772/63952

  • Bell S, Peng H, Crapper L, Kolobova I, Maussion G et. al. (2017).A Rapid Pipeline to Model Rare Neuro developmental Disorderswith Simultaneous CRISPR/Cas9 Gene Editing. Stem cellstranslational medicine, 6(3), 886–896. Doi: https://doi.org/10.1002/sctm.16-0158

  • Bevilacqua L, Goldman D (2009). Genes and addictions. Clinicalpharmacology and therapeutics. 85(4), 359–361. Doi: https://doi.org/10.1038/clpt.2009.6

  • Bonnerjee D, Bagh S (2021). Application of CRISPR-Cas systemsin neuroscience. Progress in molecularbiology and translationalscience, 178, 231–264. Doi: https://doi.org/10.1016/bs.pmbts.2020.12.010

  • Cadet JL (2016). Epigenetics of Stress, Addiction, and Resilience:Therapeutic Implications. Molecular Neurobiology. 53(1), 545– 560. Doi: https://doi.org/10.1007/s12035-014-9040-y

  • Camilo C, Maschietto M, Vieira HC, Tahira AC, Gouveia GR et.al. (2019). Genome-wide DNA methylation profile in theperipheral blood of cocaine and crack dependents. Brazilian Journal of Psychiatry. Doi:10.1590/1516-4446-2018-0092

  • Carpenter MD, Hu Q, Bond AM, Lombroso SI, Czarnecki KS et.al. (2020). Nr4a1 suppresses cocaine-induced behavior viaepigenetic regulation of homeostatic target genes. Naturecommunications, 11(1), 504. Doi: https://doi.org/10.1038/s41467-020-14331-y

  • Casas-Mollano JA, Zinselmeier MH, Erickson SE, Smanski MJ(2020). CRISPR-Cas Activators for Engineering Gene Expressionin Higher Eukaryotes. The CRISPR journal, 3(5), 350–364. Doi: https://doi.org/10.1089/crispr.2020.0064

  • Cheng Y, He C, Wang M, Ma X, Mo F et. al. (2019). Targetingepigenetic regulators for cancer therapy: mechanisms andadvances in clinical trials. Signal Transduction and TargetedTherapy. 4(1). Doi: https://doi.org/10.1038/s41392-019-0095-0

  • Covington HE, 3rd Maze I, Sun H, Bomze HM, DeMaio KD et.al. (2011). A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron. 71(4), 656–670. Doi: https://doi.org/10.1016/j.neuron.2011.06.007

  • D’Addario C, Maccarrone M (2016). Alcohol and EpigeneticModulations. Molecular Aspects of Alcohol and Nutrition. 261–273. Doi: https://doi.org/10.1016/B978-0-12-800773-0.00021-5

  • Dackis CA, O'Brien CP (2001). Cocaine dependence: a disease ofthe brain's reward centers. Journal of Substance AbuseTreatment. 21(3), 111–117. Doi: https://doi.org/10.1016/s0740- 5472(01)00192-1

  • De Sa Nogueira D, Merienne K, Befort K (2019).Neuroepigenetics and addictive behaviors: Where do westand? Neuroscience and Biobehavioral Reviews. 106, 58–72. Doi: https://doi.org/10.1016/j.neubiorev.2018.08.018

  • DeBaker MC, Marron Fernandez de Velasco E, McCall NM, LeeAM, Wickman K (2021). Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental AreaDopamine Neurons on Behavioral Sensitivity to Cocaine andMorphine. eNeuro. 8(2), ENEURO.0081-21.2021. Doi: https://doi.org/10.1523/ENEURO.0081-21.2021

  • Disorders: From Genetics to Functional Pathways. Trends inNeurosciences, 43(8), 608–621. Doi: https://doi.org/10.1016/j.tins.2020.05.004

  • Du X, Parent JM (2015). Using Patient-Derived InducedPluripotent Stem Cells to Model and Treat Epilepsies. Currentneurology and neuroscience reports, 15(10), 71. Doi: https://doi.org/10.1007/s11910-015-0588-3

  • Fontana J, Sparkman-Yager D, Zalatan JG, Carothers JM (2020).Challenges and opportunities with CRISPR activation in bacteriafor data-driven metabolic engineering. Current Opinion inBiotechnology. 64, 190–198. Doi:10.1016/j.copbio.2020.04.005

  • Fukushima HS, Takeda H, Nakamura R (2019). Targeted in vivoepigenome editing of H3K27me3. Epigenetics &Chromatin 12, 17. Doi: https://doi.org/10.1186/s13072-019- 0263-z

  • Gasiunas G, Barrangou R, Horvath P, Siksnys V (2012). Cas9-crRNA ribonucleo protein complex mediates specific DNAcleavage for adaptive immunity in bacteria. Proceedings of theNational Academy of Sciences of the United States ofAmerica. 109(39), E2579–E2586. Doi: https://doi.org/10.1073/pnas.1208507109

  • Gibney ER, Nolan CM (2010). Epigenetics and gene expression.Heredity, 105(1), 4–13. Doi: https://doi.org/10.1038/hdy.2010.54Godino A, Jayanthi S, Cadet JL (2015). Epigenetic landscape ofamphetamine and methamphetamine addiction in rodents.Epigenetics. 10(7), 574– 580. Doi:10.1080/15592294.2015.1055441

  • Grzywacz A, Barczak W, Chmielowiec J, Chmielowiec K,Suchanecka A et. al. (2020). Contribution of DopamineTransporter Gene Methylation Status to Cannabis Dependency. Brain Sciences. 10(6), 400. Doi:10.3390/brainsci10060400

  • Gu Y, Cao H, Li F, Yu J, Nian R et al. (2020). Production offunctional human nerve growth factor from the submandibularglands of mice using a CRISPR/Cas9 genome editingsystem. World Journal Microbiology Biotechnology 36, 176 (2020). Doi: https://doi.org/10.1007/s11274-020-02951-x

  • Haas C, Karila L, Lowenstein W (2009). Addiction a la cocaïne etau "crack": un problème de santé publique qui s'aggrave [Cocaineand crack addiction: a growing public health problem]. Bulletin de l'Academie nationale de medecine. 193(4), 947–963.

  • Hamilton PJ, Lim CJ, Nestler EJ, Heller E A (2018).Neuroepigenetic Editing. Methods in molecularbiology (Clifton,N.J.), 1767, 113–136. Doi: https://doi.org/10.1007/978-1-4939- 7774-1_5

  • Hamilton PJ, Nestler EJ (2019). Epigenetics and addiction.Current Opinion in Neurobiology. 59, 128–136. Doi: 10.1016/j.conb.2019.05.005

  • Hana S, Peterson M, McLaughlin H, Marshall E, Fabian A etal. (2021). Highly efficient neuronal gene knockout in vivo byCRISPR-Cas9 via neonatal intra cerebro ventricular injection ofAAV in mice. Gene Therapy. Doi: https://doi.org/10.1038/s41434-021-00224-2

  • Handel AE, Disanto G, Ramagopalan SV (2013). Next-generation sequencing in understanding complex neurologicaldisease. Expert review of neurotherapeutics. 13(2), 215–227. Doi: https://doi.org/10.1586/ern.12.165

  • Heidenreich M, Zhang F (2015). Applications of CRISPR–Cassystems in neuroscience. Nature Reviews Neuroscience. 17(1), 36–44. Doi:10.1038/nrn.2015.2

  • Heidenreich M, Zhang F (2016). Applications of CRISPR-Cassystems in neuroscience. Nature reviews. Neuroscience, 17 (1), 36–44. Doi: https://doi.org/10.1038/nrn.2015.2

  • Heller EA, Cates HM, Peña CJ, Sun H, Shao N et. al.(2014). Locus-specific epigenetic remodeling controls addiction-and depression-related behaviors. Nature Neuroscience. 17(12), 1720–1727. Doi: 10.1038/nn.3871

  • Hryhorowicz M, Lipiński D, Zeyland J, Słomski R (2017).CRISPR/Cas9 Immune System as a Toolfor GenomeEngineering. Archivum immunologiae et therapiaeexperimentalis. 65(3), 233–240. Doi:Hsu MN, Liao HT, Truong VA, Huang KL, Yu FJ et. al. (2019).CRISPR-based Activation of Endogenous Neurotrophic Genes inAdipose Stem Cell Sheets to Stimulate Peripheral NerveRegeneration. Theranostics, 9(21), 6099–6111. Doi: https://doi.org/10.7150/thno.36790

  • Hsu PD, Lander ES, Zhang F (2014). Development andapplications of CRISPR-Cas9 for genomeengineering. Cell. 157(6), 1262–1278. Doi: https://doi.org/10.1016/j.cell.2014.05.010

  • Huang YH, Schlüter OM, Dong Y (2011). Cocaine-inducedhomeostatic regulation and dysregulation of nucleus accumbensneurons. Behavioural brain research, 216(1), 9–18. Doi: https://doi.org/10.1016/j.bbr.2010.07.039

  • Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A(1987). Nucleotidesequence of theiap gene, responsible foralkaline phosphatase isozyme conversion in Escherichia coli, andidentification of the gene product. Journal ofbacteriology, 169(12), 5429–5433. Doi: https://doi.org/10.1128/jb.169.12.5429-5433.1987

  • Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA et. al.(2012). A programmable dual-RNA-guided DNA endonucleasein adaptive bacterial immunity. Science (New York,N.Y.), 337(6096), 816–821. Doi: https://doi.org/10.1126/science.1225829

  • Kim S, Kaang BK (2017). Epigenetics regulation and chromatinremodeling in learning and memory.Experimental&MolecularMedicine, 49(1), e281–e281. Doi: https://doi.org/10.1038/emm.2016.140

  • Klein M (1998). Research Issues Related to Development ofMedications for Treatment of Cocaine Addiction. Annals of theNew York Academy of Sciences. 844(1), 75– 91. Doi:10.1111/j.1749-6632.1998.tb08223.x

  • Kwon DY, Zhao YT, Lamonica JM, Zhou Z (2017). Locus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC. Nature Communications. 8, 15315. Doi:10.1038/ncomms15315

  • Li H, Yang Y, Hong W, Huang M, Wu M et. al. Applications ofgenome editing technology in the targeted therapy of humandiseases: mechanisms, advances and prospects. SignalTransduction and Targeted Therapy. 5, 1 (2020). Doi: https://doi.org/10.1038/s41392-019-0089-y

  • Li Q, Qin Z, Wang Q, Xu T, Yang Y et. al. (2019). Applications ofGenome Editing Technology in Animal Disease Modeling andGene Therapy. Computational and structural biotechnologyjournal. 17, 689–698. Doi: https://doi.org/10.1016/j.csbj.2019.05.006

  • Liu KI, Sutrisnoh NB, Wang Y, Tan MH (2019). Genome Editingin Mammalian Cell Linesusing CRISPR-Cas. Journal ofvisualized experiments : JoVE, (146), 10.3791/59086. Doi: https://doi.org/10.3791/59086

  • Lopez-Guerrero AM, Pascual-Caro C, Martin-Romero FJ, Pozo-Guisado E (2017). Store-operated calcium entry is dispensablefor the activation of ERK1/2 pathway in prostate cancer cells.Cellular Signalling. 40, 44–52. Doi: https://doi.org/10.1016/j.cellsig.2017.08.010

  • Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K et. al.(2016). Epigenetic Perturbations by Arg882-Mutated DNMT3A

  • Potentiate Aberrant Stem Cell Gene-Expression Program andAcute Leukemia Development. Cancer Cell. 30(1), 92–107. Doi: 10.1016/j.ccell.2016.05.008

  • Maze I, Covington HE, Dietz DM, LaPlant Q, Renthal W et. al.(2010). Essential Role of the Histone Methyltransferase G9a inCocaine-Induced Plasticity. Science. 327(5962), 213– 216. Doi:10.1126/science.1179438

  • McDonald JI, Celik H, Rois LE, Fishberger G, Fowler T et. al.(2016). Reprogrammable CRISPR/Cas9-based system forinducing site-specific DNA methylation. Biology Open. 5(6), 866–874. Doi:10.1242/bio.019067

  • Miller JL, Grant PA (2012). The Role of DNA Methylation andHistone Modifications in Transcriptional Regulation in Humans.Epigenetics: Development and Disease. 289– 317. Doi:10.1007/978-94-007-4525-4_13

  • Moore LD, Le T, Fan G (2012). DNA Methylation and Its BasicFunction. Neuropsychopharmacology, 38(1), 23–38. 10.1038/npp.2012.112

  • Nakamura M, Gao Y, Dominguez AA, Qi LS (2021). CRISPRtechnologies for precise epigenome editing. Nature CellBiology. 23, 11–22. Doi: https://doi.org/10.1038/s41556-020- 00620-7

  • Nambiar TS, Billon P, Diedenhofen G, Hayward SB, TaglialatelaA et al. Stimulation of CRISPR-mediated homology-directedrepair by an engineered RAD18 variant. NatureCommunications. 10, 3395 (2019). Doi: https://doi.org/10.1038/s41467-019-11105-z

  • Nestler EJ (2004). Molecular mechanisms of drug addiction.Neuropharmacology. 47, 24– 32. Doi:10.1016/j.neuropharm.2004.06

  • Nestler EJ (2014). Epigenetic mechanisms of drug addiction.Neuropharmacology, 76, 259– 268. 10.1016/j.neuropharm.2013.04.004

  • Nestler EJ, Barrot M, Self DW (2001). FosB: A sustainedmolecular switch for addiction. Proceedings of the NationalAcademy of Sciences. 98(20), 11042– 11046. Doi:10.1073/pnas.191352698

  • Nidhi S, Anand U, Oleksak P, Tripathi P, Lal JA et. al. (2021).Novel CRISPR-Cas Systems: An UpdatedReview oftheCurrentAchievements, Applications, andFutureResearchPerspectives. International journal ofmolecularsciences, 22(7), 3327. Doi: https://doi.org/10.3390/ijms22073327

  • Nielsen DA, Utrankar A, Reyes JA, Simons DD, Kosten TR(2012). Epigenetics of drugabuse: predispositionor response.Pharmacogenomics, 13(10), 1149–1160. Doi:10.2217/pgs.12.94

  • (2012). Epigenetics of drug abuse: predisposition or response.Pharmacogenomics. 13(10), 1149–1160. Doi:10.2217/pgs.12.94

  • Nishiyama J (2019). Genome editing in the mammalian brainusing the CRISPR-Cas system. Neuroscienceresearch, 141, 4–12. Doi: https://doi.org/10.1016/j.neures.2018.07.003

  • Nuñez JK, Chen J, Pommier GC, Cogan JZ, Replogle JM et. al.(2021). Genome-wide programmable transcriptional memory byCRISPR-based epigenome editing. Cell. 184(9), 2503–2519.e17. Doi: https://doi.org/10.1016/j.cell.2021.03.025

  • O’Brien J, Hayder H, Zayed Y, Peng C (2018). Overview ofMicroRNA Biogenesis, Mechanisms of Actions, and Circulation.Frontiers in Endocrinology, 9. Doi: https://doi.org/10.3389/fendo.2018.00402

  • Osella M, Riba A, Testori A, Corà D, Caselle M (2014). Interplayof microRNA and epigeneticregulation in thehumanregulatorynetwork. Frontiers in Genetics, 5. Doi: https://doi.org/10.3389/fgene.2014.00345

  • Parenti I, Rabaneda LG, Schoen H, Novarino G (2020). Neuro developmental

  • Peter CJ, Saito A, Hasegawa Y, Tanaka Y, Nagpal M et. al. (2019).In vivo epigenetic editing of Sema6a promoter reversestranscallosal dysconnectivity caused by C11orf46/Arl14ep riskgene. Nature communications, 10 (1), 4112. Doi:Ptak C, Petronis A (2010). Epigenetic approaches to psychiatricdisorders. Dialogues in clinical neurosciartorence, 12(1), 25–35. Doi: https://doi.org/10.31887/DCNS.2010.12.1/cptak

  • Pulecio J, Verma N, Mejía-Ramírez E, Huangfu D, Raya A(2017). CRISPR/Cas9-Based Engineering of the Epigenome. Cellstem cell. 21(4), 431–447. Doi: https://doi.org/10.1016/j.stem.2017.09.006

  • Renthal W, Nestler EJ (2010). Histone acetylation in drugaddiction. Seminars in Cell & Developmental Biology, 20(4), 387–394. Doi:10.1016/j.semcdb.2009.01.005

  • Riancho J, Del Real A, Riancho JA (2016). How to interpretepigenetic association studies: a guide for clinicians. BoneKEyreports. 5, 797. Doi: https://doi.org/10.1038/bonekey.2016.24

  • Robinson T, Brambilla R, Yang P, Fasano S, Ferguson S (2006).Knockout of ERK1 Enhances Cocaine-Evoked Immediate EarlyGene Expression and Behavioral Plasticity. Neuropsychopharmacology. 2660-2668.

  • Rodríguez-Rodríguez DR, Ramírez-Solís R, Garza-Elizondo MA,Garza-Rodríguez ML, Barrera-Saldaña HA (2019).Genomeediting: A perspective on theapplication ofCRISPR/Cas9 to study human diseases (Review). Internationaljournal of molecular medicine. 43(4), 1559–1574. Doi: https://doi.org/10.3892/ijmm.2019.4112

  • Sabitha KR, Shetty AK, Upadhya D (2021). Patient-derived iPSCmodeling of rare neuro developmental disorders: Molecularpathophysiology and prospective therapies. Neuroscience andbio behavioral reviews, 121, 201–219. Doi: https://doi.org/10.1016/j.neubiorev.2020.12.025

  • Sadri-Vakili G (2015). Cocaine triggers epigenetic alterations inthe corticostriatal circuit. Brain Research. 1628, 50– 59. Doi:10.1016/j.brainres.2014.09.06

  • Samaha AN (2004). The Rate of Cocaine Administration AltersGene Regulation and Behavioral Plasticity: Implications forAddiction. Journal of Neuroscience. 24(28), 6362– 6370. Doi:10.1523/jneurosci.1205-04.2004

  • Sandoval Jr A, Elahi H, Ploski JE (2020). Genetically Engineeringthe Nervous System with CRISPR-Cas. eNeuro, 7(2),ENEURO.0419-19.2020. Doi: https://doi.org/10.1523/ENEURO.0419-19.2020

  • Sartor GC (2019). Epigenetic pharmacotherapy for substance usedisorder. Biochemical Pharmacology. 168, 269–274. Doi: https://doi.org/10.1016/j.bcp.2019.07.012

  • Shinkai Y, Tachibana M (2011). H3K9 methyltransferase G9aand the related molecule GLP. Genes and Development. 25(8), 781–788. Doi: 10.1101/gad.2027411

  • Straub C, Granger AJ, Saulnier JL, Sabatini BL (2014).CRISPR/Cas9-mediated gene knock-down in post-mitoticneurons. PloSone, 9(8), e105584. Doi: https://doi.org/10.1371/journal.pone.0105584

  • Swiech L, Heidenreich M, Banerjee A, Habib N, Li Y et. al.(2015). In vivo interrogation of gene function in the mammalianbrain using CRISPR-Cas9. Nature Biotechnology. 33(1), 102– 106. Doi: https://doi.org/10.1038/nbt.3055

  • Thakore PI, Black JB, Hilton IB, Gersbach CA (2016). Editing theepigenome: technologies for programmable transcription andepigenetic modulation. Nature Methods. 13(2), 127–137. Doi: 10.1038/nmeth.3733

  • Trujillo CA, Muotri AR (2018). Brain Organoids and the Studyof Neurodevelopment. Trends in molecular medicine, 24(12),982–990. Doi: https://doi.org/10.1016/j.molmed.2018.09.005

  • Tuesta LM, Zhang Y (2014). Mechanisms of epigenetic memoryand addiction. The EMBO Journal. 33(10), 1091–1103. Doi: https://doi.org/10.1002/embj.201488106

  • Uddin F, Rudin CM, Sen T. (2020). CRISPR Gene Therapy:Applications, Limitations, and Implications for theFuture. Frontiers in oncology, 10, 1387. Doi: https://doi.org/10.3389/fonc.2020.01387

  • Urnov FD, Wolffe AP (2001). Chromatin remodeling andtranscriptional activation: the cast (in order of appearance).Oncogene. 20(24), 2991–3006. Doi: https://doi.org/10.1038/sj.onc.1204323

  • Vojta A, Dobrinić P, Tadić V, Bočkor L, Korać P et. al.(2016). Repurposing the CRISPR-Cas9 system for targeted DNAmethylation. Nucleic Acids Research. 44(12), 5615–5628. Doi: 10.1093/nar/gkw159

  • Wanner NM, Colwell ML, Faulk C (2019). The epigenetic legacyof illicit drugs: developmental exposures and late-lifephenotypes. Environmental Epigenetics. 5(4), dvz022. Doi: https://doi.org/10.1093/eep/dvz022

  • Wei JW, Huang K, Yang C, Kang CS (2016). Non-codingRNAsas regulators in epigenetics. OncologyReports, 37(1), 3–9. Doi: https://doi.org/10.3892/or.2016.5236

  • Wong CC, Caspi A, Williams B, Craig IW, Houts R et. al. (2010).A longitudinal study of epigenetic variation intwins. Epigenetics, 5(6), 516–526. Doi: https://doi.org/10.4161/epi.5.6.12226

  • Wu X, Kriz AJ, Sharp PA (2014). Target specificity of theCRISPR-Cas9 system. Quantitative biology (Beijing,China), 2(2), 59–70. Doi: https://doi.org/10.1007/s40484-014- 0030-x

  • Xie N, Zhou Y, Sun Q, Tang B (2018).NovelEpigeneticTechniquesProvided by the CRISPR/Cas9System. Stem cells international, 2018, 7834175. Doi: https://doi.org/10.1155/2018/7834175

  • Xiong X, Chen M, Lim WA, Zhao D, Qi LS (2016).CRISPR/Cas9 for Human Genome Engineering and DiseaseResearch. Annual review of genomics and humangenetics. 17,131–154. Doi: https://doi.org/10.1146/annurev-genom-083115-Yamaguchi H, Hopf FW, Li SB, de Lecea L (2018). In vivo celltype-specific CRISPR knockdown of dopamine beta hydroxylasereduces locus coeruleus evoked wakefulness. NatureCommunications. 9(1), 5211. Doi:Yeh E, Dao DQ, Wu ZY, Kandalam SM, Camacho FM et. al.(2018). Patient-derived iPSCs show premature neuraldifferentiation and neuron type-specific phenotypes relevant toneuro development. Molecularpsychiatry, 23(8), 1687–1698. Doi: https://doi.org/10.1038/mp.2017.238

  • Yim YY, Teague CD, Nestler EJ (2020). In vivo locus-specificediting of the neuro epigenome. Nature RewiesNeuroscience. 21, 471–484. Doi: https://doi.org/10.1038/s41583- 020-0334-y

  • Yu C, Zhou X, Fu Q, Peng Q, Oh KW et. al. (2017). A NewInsight into the Role of CART in Cocaine Reward: Involvementof CaMKII and Inhibitory G-Protein Coupled ReceptorSignaling. Frontiers in cellular neuroscience, 11, 244. Doi: https://doi.org/10.3389/fncel.2017.00244

  • Zhao Z, Ukidve A, Kim J, Mitragotri S (2020). TargetingStrategies for Tissue-Specific Drug Delivery. Cell. 181(1), 151– 167. Doi: https://doi.org/10.1016/j.cell.2020.02.001

  • Zovkic IB, Guzman-Karlsson MC, Sweatt JD(2013). Epigeneticregulation of memory formation andmaintenance. Learning & Memory, 20(2), 61–74. 10.1101/lm.026575.112

                                                                                                                                                                                                        
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