ReviewControllingtheControllers:RegulationofHistoneMethylationbyPhosphosignallingRyanJ.Separovich,1ChiNamIgnatiusPang,1andMarcR.Wilkins1,*Histonemethylationiscentraltotheregulationofeukaryotictranscription.Here,wereviewhowthehistonemethylationsystemitselfisregulated.Thereissub-stantialevidencethatmammalianhistonemethyltransferasesanddemethylasesarephosphorylatedandregulatedbyupstreamsignallingpathways.Functionalstudiesofspecificphosphositesarerevealingwhichkinasesandpathwayssignaltothehistonemethylationsystemandarediscoveringthediverseeffectsofphos-phorylationonenzymefunction.Nevertheless,themajorityofphosphositeshavenoknownkinaseorfunctionandourunderstandingofhowhistonemethylationisregulatedisfragmentary.Improvedapproachesareneededtoestablishandstudythekeyregulatoryphosphorylationsitesonhistonemethyltransferasesanddemethylases,toavoidfocusonconstitutivesiteswhichmayhavelittleregulatorypurpose.HistoneMethylationIsaCentralRegulatoryProcessintheEukaryoticCellEukaryoticcellsrespondtointernalandexternalstimuliviasignallingsystems.Associatedchangesingeneexpressionaremediatedbyepigeneticmodifications(seeGlossary)ofhistoneproteins,whichaffectchromatincompactionandtherecruitmentoftranscriptionalcoregulators[1].Histonemethylationisakeyepigeneticmodificationthatregulatesmanynuclearprocesses,includingtranscription[2],replication[3],andDNArepair[4].Specifichistonemethylmarkscanhaveeitheractivatingorrepressiveeffectsontranscriptiondependingontheirpositionandmethylationstate[2].Alleukaryotichistonemethylationsitesdemarcatefunctionalsequencesinthegenome,boththroughoutagene’sbodyandwithinnoncodingandregulatoryelements,suchaspromotersandenhancers[5,6].Importantly,thegenomicdistributionofhistonemethylationchangesdramaticallyduringgrowth[7],differentiation[8],andinresponsetoexogenousperturbation[9],tobringaboutwidespreadtranscriptionalreprogramming.Despiteitsmajorregulatoryrole,littleisknownabouthowhistonemethylationasasystemreceivesinformationfromupstreamsignallingpathways.Assuch...
