LeadingapproachesinsyntheticepigeneticsfornoveltherapeuticstrategiesKenzoYamatsugu1,2,ShigehiroAKawashima1,2andMotomuKanai1,2Inrecentyears,ourknowledgeoftheepigeneticfunctionsregulatedbypost-translationalmodifications(PTMs)ofhistones,andtheirroleinvariousdiseases,hasexpandedrapidly,openingthewaytonoveltherapeuticstrategiesthattreatepigeneticabnormalities.Manyofthecurrentapproacheshavebeenfocusingonthechemicalinhibitionofhistone-modifyingenzymestomodulatehistonePTMstatesforattainingtherapeuticeffects.However,recentdevelopmentsinchemistryandmolecularbiologyhavecontributedtotheemergenceofnewmethodsthatintroducehistonePTMsentirelythroughartificialmeans,withoutrelianceonendogenousenzymes.Inthisreviewarticle,wesummarizeseveralstate-of-the-artapproachesfortheintroductionofsyntheticepigeneticmodificationsincells,anddiscussboththeirtherapeuticpotentialandthepossiblechallengesindevelopingnoveltherapeuticstrategiesutilizingthem.Addresses1GraduateSchoolofPharmaceuticalSciences,TheUniversityofTokyo,7-3-1Hongo,Bunkyo-ku,Tokyo113-0033,Japan2JST-ERATO,JapanCorrespondingauthors:Yamatsugu,Kenzo(yamatsugu@mol.f.u-tokyo.ac.jp),Kawashima,ShigehiroA(skawashima@mol.f.u-tokyo.ac.jp),Kanai,Motomu(kanai@mol.f.u-tokyo.ac.jp)CurrentOpinioninChemicalBiology2018,46:10–17ThisreviewcomesfromathemedissueonSyntheticbiomoleculesEditedbyRichardJPayneandNicolasWinssingerhttps://doi.org/10.1016/j.cbpa.2018.03.0111367-5931/ã2018ElsevierLtd.Allrightsreserved.IntroductionOurgeneticinformation,encodedinDNA,ispackagedinthecellnucleusinapolymericcomplexcalledchromatin.Thefundamentalunitofchromatinisanucleosome,composedofhistoneproteins(H2A,H2B,H3,andH4)andtheDNAwrappedaroundthem[1].ThefunctionofthechromatinisregulatedbychemicalmodificationsofitshistonesandDNA,intheformoflysineacetylation,lysinemethylation,andcytosinemethylation,amongothers.Thesechemicalmodificationseitherdirectlyaffectthestructureofthechromatin[2]orarerecognizedbyothereffectorproteins[3],leadingtotheregulationofgeneexpression,whichisafun...
