Editing Epigenetics (section)

==Research==
The two forms of heritable information, namely genetic and epigenetic, are collectively called dual inheritance. Members of the APOBEC/AID family of [[cytosine deaminase]]s may concurrently influence genetic and epigenetic inheritance using similar molecular mechanisms, and may be a point of crosstalk between these conceptually compartmentalized processes.<ref name="pmid20800313">{{cite journal | vauthors = Chahwan R, Wontakal SN, Roa S | title = Crosstalk between genetic and epigenetic information through cytosine deamination | journal = Trends in Genetics | volume = 26 | issue = 10 | pages = 443–8 | date = October 2010 | pmid = 20800313 | doi = 10.1016/j.tig.2010.07.005 }}</ref>

[[Fluoroquinolone]] antibiotics induce epigenetic changes in [[mammalian]] cells through iron [[chelation]]. This leads to epigenetic effects through inhibition of α-ketoglutarate-dependent [[dioxygenases]] that require [[iron]] as a co-factor.<ref>{{cite journal | vauthors = Badal S, Her YF, Maher LJ | title = Nonantibiotic Effects of Fluoroquinolones in Mammalian Cells | journal = The Journal of Biological Chemistry | volume = 290 | issue = 36 | pages = 22287–97 | date = September 2015 | pmid = 26205818 | pmc = 4571980 | doi = 10.1074/jbc.M115.671222 | doi-access = free }}</ref>

Various pharmacological agents are applied for the production of induced pluripotent stem cells (iPSC) or maintain the embryonic stem cell (ESC) phenotypic via epigenetic approach. Adult stem cells like bone marrow stem cells have also shown a potential to differentiate into cardiac competent cells when treated with G9a histone methyltransferase inhibitor BIX01294.<ref>{{cite journal | vauthors = Mezentseva NV, Yang J, Kaur K, Iaffaldano G, Rémond MC, Eisenberg CA, Eisenberg LM | title = The histone methyltransferase inhibitor BIX01294 enhances the cardiac potential of bone marrow cells | journal = Stem Cells and Development | volume = 22 | issue = 4 | pages = 654–67 | date = February 2013 | pmid = 22994322 | pmc = 3564468 | doi = 10.1089/scd.2012.0181 }}</ref><ref>{{cite journal | vauthors = Yang J, Kaur K, Ong LL, Eisenberg CA, Eisenberg LM | title = Inhibition of G9a Histone Methyltransferase Converts Bone Marrow Mesenchymal Stem Cells to Cardiac Competent Progenitors | journal = Stem Cells International | volume = 2015 | pages = 270428 | date = 2015 | pmid = 26089912 | pmc = 4454756 | doi = 10.1155/2015/270428 | doi-access = free }}</ref>

Cell plasticity, which is the adaptation of cells to stimuli without changes in their genetic code, requires epigenetic changes. These have been observed in cell plasticity in cancer cells during epithelial-to-mesenchymal transition<ref>{{cite journal | vauthors = Müller S, Sindikubwabo F, Cañeque T, Lafon A, Versini A, Lombard B, Loew D, Wu TD, Ginestier C, Charafe-Jauffret E, Durand A, Vallot C, Baulande S, Servant N, Rodriguez R | title = CD44 regulates epigenetic plasticity by mediating iron endocytosis | journal = Nature Chemistry | volume = 12 | issue = 10 | pages = 929–938 | date = October 2020 | doi = 10.1038/s41557-020-0513-5 | pmid = 32747755 | pmc = 7612580 | bibcode = 2020NatCh..12..929M }}</ref> and also in immune cells, such as macrophages.<ref>{{cite journal | vauthors = Solier S, Müller S, Cañeque T, Versini A, Mansart A, Sindikubwabo F, Baron L, Emam L, Gestraud P, Pantoș GD, Gandon V, Gaillet C, Wu TD, Dingli F, Loew D, Baulande S, Durand S, Sencio V, Robil C, Trottein F, Péricat D, Näser E, Cougoule C, Meunier E, Bègue AL, Salmon H, Manel N, Puisieux A, Watson S, Dawson MA, Servant N, Kroemer G, Annane D, Rodriguez R | title = A druggable copper-signalling pathway that drives inflammation | journal = Nature | volume = 617 | issue = 7960 | pages = 386–394 | date = May 2023 | pmid = 37100912 | doi = 10.1038/s41586-023-06017-4 | pmc = 10131557 | bibcode = 2023Natur.617..386S }}</ref> Interestingly, metabolic changes underlie these adaptations, since various metabolites play crucial roles in the chemistry of epigenetic marks. This includes for instance alpha-ketoglutarate, which is required for histone demethylation, and acetyl-Coenzyme A, which is required for histone acetylation.

===Epigenome editing===
{{Main|Epigenome editing}} 
Epigenetic regulation of gene expression that could be altered or used in [[epigenome editing]] are or include [[mRNA modification|mRNA/lncRNA modification]], [[DNA methylation]] modification and [[histone modification]].<ref>{{cite journal | vauthors = Liu N, Pan T | title = RNA epigenetics | journal = Translational Research | volume = 165 | issue = 1 | pages = 28–35 | date = January 2015 | pmid = 24768686 | pmc = 4190089 | doi = 10.1016/j.trsl.2014.04.003 }}</ref><ref>{{cite journal | vauthors = Rong D, Sun G, Wu F, Cheng Y, Sun G, Jiang W, Li X, Zhong Y, Wu L, Zhang C, Tang W, Wang X | title = Epigenetics: Roles and therapeutic implications of non-coding RNA modifications in human cancers | journal = Molecular Therapy. Nucleic Acids | volume = 25 | pages = 67–82 | date = September 2021 | pmid = 34188972 | pmc = 8217334 | doi = 10.1016/j.omtn.2021.04.021 | s2cid = 235558945 }}</ref><ref>{{cite journal | vauthors = Shin H, Choi WL, Lim JY, Huh JH | title = Epigenome editing: targeted manipulation of epigenetic modifications in plants | journal = Genes & Genomics | volume = 44 | issue = 3 | pages = 307–315 | date = March 2022 | pmid = 35000141 | doi = 10.1007/s13258-021-01199-5 | s2cid = 245848779 }}</ref>

=== CpG sites, SNPs and biological traits ===
Methylation is a widely characterized mechanism of genetic regulation that can determine biological traits. However, strong experimental evidences correlate methylation patterns in SNPs as an important additional feature for the classical activation/inhibition epigenetic dogma. Molecular interaction data, supported by colocalization analyses, identify multiple nuclear regulatory pathways, linking sequence variation to disturbances in DNA methylation and molecular and phenotypic variation.<ref name="Hawe_2022">{{cite journal | vauthors = Hawe JS, Wilson R, Schmid KT, Zhou L, Lakshmanan LN, Lehne BC, Kühnel B, Scott WR, Wielscher M, Yew YW, Baumbach C, Lee DP, Marouli E, Bernard M, Pfeiffer L, Matías-García PR, Autio MI, Bourgeois S, Herder C, Karhunen V, Meitinger T, Prokisch H, Rathmann W, Roden M, Sebert S, Shin J, Strauch K, Zhang W, Tan WL, Hauck SM, Merl-Pham J, Grallert H, Barbosa EG, Illig T, Peters A, Paus T, Pausova Z, Deloukas P, Foo RS, Jarvelin MR, Kooner JS, Loh M, Heinig M, Gieger C, Waldenberger M, Chambers JC | title = Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function | journal = Nature Genetics | volume = 54 | issue = 1 | pages = 18–29 | date = January 2022 | pmid = 34980917 | doi = 10.1038/s41588-021-00969-x | s2cid = 245654240 | url = https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=64018 | access-date = 20 January 2023 | archive-date = 29 October 2022 | archive-url = https://web.archive.org/web/20221029233638/https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=64018 | url-status = dead | pmc = 7617265 }}</ref>

==== ''UBASH3B'' locus ====
''UBASH3B'' encodes a protein with tyrosine phosphatase activity, which has been previously linked to advanced neoplasia.<ref>{{cite journal | vauthors = Lee ST, Feng M, Wei Y, Li Z, Qiao Y, Guan P, Jiang X, Wong CH, Huynh K, Wang J, Li J, Karuturi KM, Tan EY, Hoon DS, Kang Y, Yu Q | title = Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 27 | pages = 11121–11126 | date = July 2013 | pmid = 23784775 | doi = 10.1073/pnas.1300873110 | pmc = 3704014 | bibcode = 2013PNAS..11011121L | doi-access = free }}</ref> SNP rs7115089 was identified as influencing DNA methylation and expression of this locus, as well as and Body Mass Index (BMI).<ref name="Hawe_2022" /> In fact, SNP rs7115089 is strongly associated with BMI<ref>{{cite journal | vauthors = Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, Frayling TM, Hirschhorn J, Yang J, Visscher PM | title = Meta-analysis of genome-wide association studies for height and body mass index in ~700000 individuals of European ancestry | journal = Human Molecular Genetics | volume = 27 | issue = 20 | pages = 3641–3649 | date = October 2018 | pmid = 30124842 | doi = 10.1093/hmg/ddy271 | pmc = 6488973 }}</ref> and with genetic variants linked to other cardiovascular and metabolic traits in GWASs.<ref>{{cite journal | vauthors = Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, Yengo L, Ferreira T, Marouli E, Ji Y, Yang J, Jones S, Beaumont R, Croteau-Chonka DC, Winkler TW, Hattersley AT, Loos RJ, Hirschhorn JN, Visscher PM, Frayling TM, Yaghootkar H, Lindgren CM | title = Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry | journal = Human Molecular Genetics | volume = 28 | issue = 1 | pages = 166–174 | date = January 2019 | pmid = 30239722 | doi = 10.1093/hmg/ddy327 | pmc = 6298238 }}</ref><ref>{{cite journal | vauthors = Zhu Z, Guo Y, Shi H, Liu CL, Panganiban RA, Chung W, O'Connor LJ, Himes BE, Gazal S, Hasegawa K, Camargo CA, Qi L, Moffatt MF, Hu FB, Lu Q, Cookson WO, Liang L | title = Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank | journal = The Journal of Allergy and Clinical Immunology | volume = 145 | issue = 2 | pages = 537–549 | date = February 2020 | pmid = 31669095 | doi = 10.1016/j.jaci.2019.09.035 | pmc = 7010560 }}</ref><ref>{{cite journal | vauthors = Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, Holmes MV | title = Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis | journal = PLOS Medicine | volume = 17 | issue = 3 | pages = e1003062 | date = March 2020 | pmid = 32203549 | doi = 10.1371/journal.pmed.1003062 | pmc = 7089422 | doi-access = free }}</ref> New studies suggesting ''UBASH3B'' as a potential mediator of adiposity and cardiometabolic disease.<ref name="Hawe_2022" /> In addition, animal models demonstrated that ''UBASH3B'' expression is an indicator of caloric restriction that may drive programmed susceptibility to obesity and it is associated with other measures of adiposity in human peripherical blood.<ref>{{cite journal | vauthors = Konieczna J, Sánchez J, Palou M, Picó C, Palou A | title = Blood cell transcriptomic-based early biomarkers of adverse programming effects of gestational calorie restriction and their reversibility by leptin supplementation | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 9088 | date = March 2015 | pmid = 25766068 | doi = 10.1038/srep09088 | pmc = 4357898 | bibcode = 2015NatSR...5.9088K }}</ref>

==== ''NFKBIE'' locus ====
SNP rs730775 is located in the first intron of ''NFKBIE'' and is a ''cis'' eQTL for ''NFKBIE'' in whole blood.<ref name="Hawe_2022" /> Nuclear factor (NF)-κB inhibitor ε (NFKBIE) directly inhibits NF-κB1 activity and is significantly co-expressed with NF-κB1, also, it is associated with rheumatoid arthritis.<ref>{{cite journal | vauthors = Okada Y | title = From the era of genome analysis to the era of genomic drug discovery: a pioneering example of rheumatoid arthritis | journal = Clinical Genetics | volume = 86 | issue = 5 | pages = 432–440 | date = November 2014 | pmid = 25060537 | doi = 10.1111/cge.12465 | s2cid = 8499325 }}</ref> Colocalization analysis supports that variants for the majority of the CpG sites in SNP rs730775 cause genetic variation at the ''NFKBIE'' locus which is suggestible linked to rheumatoid arthritis through ''trans'' acting regulation of DNA methylation by NF-κB.<ref name="Hawe_2022" />

==== ''FADS1'' locus ====
Fatty acid desaturase 1 (FADS1) is a key enzyme in the metabolism of fatty acids.<ref>{{cite journal | vauthors = He Z, Zhang R, Jiang F, Zhang H, Zhao A, Xu B, Jin L, Wang T, Jia W, Jia W, Hu C | title = FADS1-FADS2 genetic polymorphisms are associated with fatty acid metabolism through changes in DNA methylation and gene expression | journal = Clinical Epigenetics | volume = 10 | issue = 1 | pages = 113 | date = August 2018 | pmid = 30157936 | pmc = 6114248 | doi = 10.1186/s13148-018-0545-5 | doi-access = free }}</ref> Moreover, rs174548 in the ''FADS1'' gene shows increased correlation with DNA methylation in people with high abundance of CD8+ T cells.<ref name="Hawe_2022" /> SNP rs174548 is strongly associated with concentrations of arachidonic acid and other metabolites in fatty acid metabolism,<ref>{{cite journal | vauthors = Guan W, Steffen BT, Lemaitre RN, Wu JH, Tanaka T, Manichaikul A, Foy M, Rich SS, Wang L, Nettleton JA, Tang W, Gu X, Bandinelli S, King IB, McKnight B, Psaty BM, Siscovick D, Djousse L, Chen YI, Ferrucci L, Fornage M, Mozafarrian D, Tsai MY, Steffen LM | title = Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium | journal = Circulation: Cardiovascular Genetics | volume = 7 | issue = 3 | pages = 321–331 | date = June 2014 | pmid = 24823311 | doi = 10.1161/circgenetics.113.000208 | pmc = 4123862 }}</ref><ref name="pmid24816252">{{cite journal | vauthors = Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, Arnold M, Erte I, Forgetta V, Yang TP, Walter K, Menni C, Chen L, Vasquez L, Valdes AM, Hyde CL, Wang V, Ziemek D, Roberts P, Xi L, Grundberg E, Waldenberger M, Richards JB, Mohney RP, Milburn MV, John SL, Trimmer J, Theis FJ, Overington JP, Suhre K, Brosnan MJ, Gieger C, Kastenmüller G, Spector TD, Soranzo N | title = An atlas of genetic influences on human blood metabolites | journal = Nature Genetics | volume = 46 | issue = 6 | pages = 543–550 | date = June 2014 | pmid = 24816252 | pmc = 4064254 | doi = 10.1038/ng.2982 }}</ref> blood eosinophil counts.<ref>{{Cite journal | vauthors = Astle WJ, ((UK Blood Trait GWAS Team)), ((Cambridge BLUEPRINT epigenome)) |date=2016-12-02 |title=A GWAS of 170,000 Individuals Identifies Thousands of Alleles Perturbing Blood Cell Traits, Many of Which Are in Super Enhancers Setting Cell Identity |journal=Blood |volume=128 |issue=22 |pages=2652 |doi=10.1182/blood.v128.22.2652.2652 |issn=0006-4971}}</ref> and inflammatory diseases such as asthma.<ref>{{cite journal | vauthors = Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, Butterworth AS, Staley JR | title = PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations | journal = Bioinformatics | volume = 35 | issue = 22 | pages = 4851–4853 | date = November 2019 | pmid = 31233103 | doi = 10.1093/bioinformatics/btz469 | pmc = 6853652 }}</ref> Interaction results indicated a correlation between rs174548 and asthma, providing new insights about fatty acid metabolism in CD8+ T cells with immune phenotypes.<ref name="Hawe_2022" />